How difficult is pregnancy in kidney transplant patients?

Reproductive function is impaired in patients with severe renal insufficiency. Most of these patients suffer from chronic anovulation and subsequently delayed conception. After transplantation, renal and endocrine functions rapidly recover, and pregnancy becomes possible. Since the first successful pregnancy in a kidney transplant recipient in 1958, hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, leading to anovulation and infertility. However, within 6 months of a kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal, and the renal allograft can adapt to the various physiologic changes of pregnancy. Pregnancy after Renal Transplantation (RT) is considered a high-risk pregnancy, associated with increased risks of pre-eclampsia, preterm delivery, Fetal Growth Restriction (FGR), and graft rejection, among other issues. The influence of immunosuppressants on the mother and fetus is also an important consideration. Successful pregnancy after a kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.

The ideal time to become pregnant after a kidney transplant
According to the American Society of Transplantation and European best-practice guidelines, the ideal time to conceive is 1 to 2 years after renal transplant if graft function is stable, proteinuria is minimal, there are no recent episodes of acute rejection, and the patient is not taking teratogenic medications. Because transplant recipients take teratogenic immunosuppressive drugs such as mycophenolate mofetil, women should be counselled to start contraception as soon as possible after a kidney transplant. Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion.

Factors that increase the risk of a poor pregnancy outcome after renal transplant
Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and conception is associated with better pregnancy outcomes.

Possible maternal complications
Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%. The risk of cesarean delivery is 5 times higher than in the general population, and the incidence rate is 43% to 64%.

Risk of Fetal Complications
The rate of live births in allograft recipients is comparable to the general population and ranges from 71 to 79%.  The incidence of preterm delivery has been reported to be as high as 40 to 60% versus 5 to 15% in the general population and occurs mostly due to maternal or fetal compromise rather than spontaneous preterm labor. High serum creatinine ≥1.7mg/dL and the presence of maternal hypertension predispose to preterm delivery. In addition, they have a high incidence of preterm birth (52 to 53%), low birth weight (42 to 46%), and IUGR (30 to 50%). Renal allograft recipients have a 13-fold higher risk of preterm deliveries, a 12-fold higher risk of low birth weight babies, and a 5-fold high risk of small for gestation babies as compared to the general population. The miscarriage rate ranges from 11 to 26% (versus 8 to 9% in the general population) but there is no higher risk of perinatal mortality in the absence of risk factors of hypertension, proteinuria, and impaired allograft dysfunction

Changes required for immune suppression before and during pregnancy
Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects. Mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone. A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in the metabolic activity of cytochrome P450 and an increase in the volume of distribution. However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

Effect of Pregnancy on Allograft Function
A normal pregnancy leads to hyperfiltration, intrarenal vasodilation, and an increase in effective plasma flow with no concomitant increase in intraglomerular pressure. There is an increase in the glomerular filtration rate by about 50% with a decrease in the serum concentration of creatinine and urea. Renal allograft can adapt to physiological changes of pregnancy with an increase in creatinine clearance of approximately 30% in the first trimester which is sustained with a small decrease in the second trimester and returns to prepregnancy level during the third trimester. Davison reported that the increase in 24-hour creatinine clearance in healthy women was comparable to allograft recipients at 10 weeks of gestation (38% versus 34%). Allograft recipients also have a higher 24-hour protein excretion as compared to healthy women which increase throughout pregnancy, becomes threefold higher by the third trimester regularly exceeding 500 mg (versus 200 mg in healthy women), and returns to prepregnancy levels at 3 months postpartum

Breast-feeding is safe in renal transplant recipients
Breastfeeding is considered safe for women with renal transplants who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breastfeeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate. It is well established now that the infants who are breastfed by mothers on prednisone, azathioprine, and cyclosporine/tacrolimus have lesser exposure via breast milk than in utero and they do not have adverse effects.

Conclusion
Renal transplant restores fertility and pregnancy requires careful planning. There should be an expansion of efforts by primary care physicians and nephrologists to include the discussion of menstrual and reproductive issues in women with renal transplants. Women of childbearing age wishing to consider pregnancy should receive complete information and counseling from the transplant team. Prepregnancy counseling with the potential risks will enable pregnancy planning and help parents make informed decisions. A multidisciplinary approach by the transplant nephrologist and maternal-fetal medicine is essential throughout pregnancy and can result in good outcomes for the mother and infant.

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