after renal transplant. However, both the American Society of Transplantation and European Transplantation Society suggest that the optimal time is after one year post transplantation [1].
If conception is achieved, the allografted kidney is able to adapt to the physiological changes of pregnancy and the elevated glomerular filtration rates. It is able to cope with the intrarenal vasodilatation allowing for greater creatinine clearance required for pregnancy [10]. Recent data demonstrated a live birth rate of around 75% in women who conceived a pregnancy after renal transplantation [6,11]. Reassuringly, the miscarriage and ectopic pregnancy rates do not differ from that of the general population [12].
Encouragingly, recent data have also shown that live birth in renal transplant recipients does not adversely affect the functioning of the graft and the long‐term survival of the woman [11]. The same study reported survival rates after a live birth in women with a renal graft as 92% at 10 years and 75% at 20 years [11].
When considering IVF treatment in renal transplant recipients, there are specific risks that clinicians should be aware of and patients should be well counseled before embarking on fertility treatment. It is important to consider that both renal transplantation and IVF are independently associated with greater risks of preterm birth, small for gestational age and perinatal mortality [13]. There are only a few case reports and series published on live births following IVF treatment in women who have been renal transplant recipients [13,14,15].
Risks of IVF and the graft recipient
Women who are renal transplant recipients are at higher risk than the general population of having their IVF treatment complicated by ovarian hyperstimulation (OHSS) [13]. Approximately 10% of gonadotropins are excreted renally [1]. Therefore, if renal clearance is not at optimal levels, gonadotropins may have an enhanced effect on renal transplant recipients, leading to OHSS. This can lead to intravascular dehydration, oliguria and deterioration of renal function and so ovarian stimulation must be well monitored and be carried out cautiously using lower gonadotropin doses [13]. Additionally, enlarged ovaries due to OHSS can lead to ureteric obstruction causing further deterioration of renal function [16].
The position of the transplanted kidney should be known prior to embarking IVF treatment. Access to the ovaries for oocyte retrieval may also be difficult if the allografted kidney is situated in the pelvis. Resultant elevated estradiol levels from ovarian stimulation may lead to higher risks of thrombo‐embolic disease in renal transplant recipients [13]. This is especially the case in some renal patients who may have pro‐thrombotic conditions such as systemic lupus erythematosus (SLE) with antiphospholipid autoantibodies.
Risks to the fetus
Renal transplant recipients are at more risk of miscarriage, preterm delivery, fetal growth restriction (FGR) and stillbirth [1]. A study of 1418 pregnancies showed a mean gestational age of 36 weeks, but 20% of babies had FGR and 10% were very low birthweight (<1.5 kg) [12]. Data from the US National Transplant Pregnancy Registry (NTPR) suggest that developmental delays have been seen in up to 26% of children over 5 years old [17].
Risk from immunosuppression
Renal transplant recipients require lifelong immunosuppression to prevent graft rejection [1]. Women should see their renal physicians before undergoing fertility treatments to ensure that their immunosuppressive treatment regimens are not teratogenic. All immunosuppressive drugs used in renal transplant recipients cross the placental circulation to the fetus [18].
Calcineurin inhibitors such as tacrolimus and cyclosporin are considered safe in pregnancy. The blood levels of these medications in neonates are approximately half of what is found in the woman [19]. The incidence of major congenital structural abnormalities in women using calcineurin inhibitors are comparable to the general population [20]. However, there are still concerns that calcineurin inhibitors may cause problems with neurodevelopment and increase the risk of childhood cancer [21,22]. Developmental delays have been found in 16% of children who were exposed to cyclosporin in utero [23]. From an obstetric perspective, there is also now evidence that cyclosporin use increases the likelihood of obstetric cholestasis. Therefore, all pregnant women receiving cyclosporin should be closely monitored from the second trimester for the development of this condition [24].
Azathioprine is also considered to be safe in pregnancy as the fetal liver lacks the enzymes to convert the drug into its active metabolite thioinosinic acid [25]. The fetus is therefore protected from its adverse side effects. Corticosteroids such as prednisolone and methylprednisolone have been found to cause fetal adrenal suppression and cleft palate at high maternal doses. They are considered to be safe in pregnancy if being used for immunosuppression or to treat allograft rejection [26]. Mycophenolate mofetil (MMF) is teratogenic, causing increased risk of miscarriage (49%) and congenital malformations (23%) such as limb anomalies, cleft palate, congenital heart defects and congenital diaphragmatic hernia [27] MMF should be stopped six weeks prior to pregnancy [28].
Maternal risks in pregnancy
Hypertension in pregnancy is reported to be common in renal transplant recipients affecting 52% to 69% of patients [20]. Pre‐eclampsia or eclampsia is also more common, with a reported incidence of 27% in renal transplant recipients [20,29]. Aspirin reduces the risk of preeclampsia and should be given to all renal transplant recipients [30].
In women with mild kidney disease, pregnancy confers little risk for renal allograft loss. However, for those with risk factors there is a significantly increased risk of irreversible graft loss as a result of the pregnancy [31]. Risk factors for graft loss include; prepregnancy hypertension, elevated prepregnancy creatinine and proteinuria [16].
If proteinuria develops in pregnancy, there is a substantial risk of venous thromboembolism. If antiphospholipid antibodies are also present (as is sometimes the case in lupus) there is a further escalation in thrombotic risk. Lupus, if active, also carries risks in pregnancy such as miscarriage, preeclampsia, thrombosis, FGR, preterm delivery and stillbirth [1].
Due to immunosuppressive therapy, the risks of urinary tract infection in pregnancy are further increased in a transplant patient. If urinary tract infections are not treated promptly and adequately, pyelonephritis may ensue [32]. Renal transplant recipients taking immunosuppressive therapy are also at increased risk of infections such as cytomegalovirus, toxoplasmosis, primary varicella, HIV, primary herpes infection and hepatitis B or C virus [1].
Lastly, anemia is common in pregnant renal transplant recipients and can be treated with iron (intravenous if necessary) and erythropoietin [13].
Management options
The renal transplant recipient should be well counseled prior to any fertility treatment. The couple must be aware of the risks involved with IVF treatment as well as the risks that may be encountered during pregnancy. Patients should be seen before planning fertility treatments by their renal physician and obstetrician in a multidisciplinary team setting. It must be decided whether IVF is appropriate and to optimize renal function and immunosuppressive therapy prior to embarking on treatment. MMF should be stopped and patients should be ideally switched to using tacrolimus or azathioprine three months before treatment (Case History 1). There may also need to be adjustment to antihypertensive therapy regimes, especially if the patient is taking ACE inhibitors.
The American Society of Transplantation Consensus Opinion advises that renal function is optimal when serum creatinine <1.5 mg/dl, with <500 mg/24 h protein excretion. There should be no concurrent infections and the woman should be using nonteratogenic immunosuppressive therapy, which is stable at maintenance levels in order for conception to be attempted [33]. In practice,
