Pregnancy in a Kidney Transplant Patient

Introduction

In 1958, Edith Helm, who received a kidney from her identical twin sister, became the first woman to successfully give birth after transplantation. Many women have since followed in her footsteps. In this “How I Treat” article, we review our approach to treating a patient from preconception counseling to postpartum care.

Patient

A 25-year-old woman with ESKD from FSGS on maintenance hemodialysis for 6 months received a living donor kidney transplant. Her creatinine stabilized at 1.0 mg/dl, proteinuria at 0.2 g/g, and BP at 110/70 mm Hg. Her medications included tacrolimus, mycophenolate mofetil (MMF), prednisone, trimethoprim-sulfamethoxazole, and atorvastatin. At 6 months post-transplant, she indicated the desire to start a family.

“Can I Become Pregnant?”

Fertility and sexual function in patients improve after kidney transplantation and by 6 months, the hypothalamic-pituitary-gonadal axis is restored to normal (1). Recipients of childbearing age are counseled pretransplant that contraception should be used if pregnancy is not desired. However, contraception use is suboptimal and unplanned pregnancy rates range from 33% to 93% (2,3). If an unplanned pregnancy occurs, close obstetric monitoring and counseling will be required, given fetal exposure to potentially teratogenic medications and increased risk of miscarriage (4).

“Will My Baby Be OK?”

The decision to pursue pregnancy is deeply personal and should be made after considering what patients can expect for their own health and that of their child-to-be. Much data on these outcomes have come from the Transplant Pregnancy Registry International (TPR), national registries, and single-center reports. Data from the 2017 TPR annual report and two meta-analyses by Deshpande et al. (5) and Shah et al. (6) are summarized in Table 1 (4). Voluntary registries and center reports are subject to selection and reporting bias and these results should be contrasted with Medicare claims data that show a lower post-transplant live birth rate of 55.4% and a lower pregnancy rate than in the general population (7).

Table 1.

Pregnancy outcomes in kidney transplant recipients

Outcome	TPR (4)	Deshpande et al. (5)	Shah et al. (6)	United States Populationa
Live births	75%	73.5% (95% CI, 72.1 to 74.9)	72.9% (95% CI, 70.0 to 75.6)	62%
Miscarriages	18%	14.0% (95% CI, 12.9 to 15.1)	15.4% (95% CI, 13.8 to 17.2)	17.1%
Neonatal deaths	1.4%	Not reported	3.8% (95% CI, 2.8 to 5.2)	0.4%
Still births	2%	2.5% (95% CI, 2.0 to 3.0)	5.1% (95% CI, 4.0 to 6.5)	0.6%
Hypertension in pregnancy	48%	54.2% (95% CI, 52.0 to 56.4)	24.2% (95% CI, 18.1 to 31.5), only pregnancy-induced hypertension reported	Not reported
Preeclampsia	31%	27.0% (95% CI, 25.2 to 28.9)	21.5% (95% CI, 18.5 to 24.9)	3.8%
Gestational diabetes mellitus	8%	8.0% (95% CI, 6.7 to 9.4)	5.7% (95% CI, 3.7 to 8.9)	9.2%
Cesarean-section	52%	56.9% (95% CI, 54.9 to 58.9)	62.6% (95% CI, 57.6 to 67.3)	31.9%
Preterm (before 37 wk)	51%	45.6% (95% CI, 43.7 to 47.5)	43.1% (95% CI, 38.7 to 47.6)	12.5%
Mean gestational age (wk)	35.9±3.4	35.6 (95% CI, 35.5 to 35.7)	34.9 (95% CI not available)	38.7
Mean birth weight (g)	2571±762	2420 (95% CI, 2395 to 2445)	2470 (95% CI not available)	3389
Acute rejection rate during pregnancy	1%	4.2%	9.4% (95% CI, 6.4 to 13.7)	Not applicable
Postpartum rejection	1.3%	Not reported	Not reported	Not applicable
Postpregnancy graft loss within 2 yr	5.6%	8.1%	9.2%	Not applicable
Birth defects	4.5%	Not reported	Not reported	Not reported

Pregnancy outcomes in kidney transplant recipients. TPR, Transplant Pregnancy Registry International; 95% CI, 95% confidence interval.

^aFrom Deshpande et al. (5) and Shah et al. (6).

The KDIGO and the European Best Practices guidelines advise delaying pregnancy until after the first and second year post-transplantation, respectively (8,9). Predictors of good maternal and fetal outcomes include a younger maternal age, stable graft function with no recent episodes of graft rejection, serum creatinine level of <1.5 mg/dl, proteinuria of <500 mg a day, and normal or well controlled hypertension (4–6,8). Data on pregnancies in less-ideal situations is lacking, and the risks of maternal harm, graft failure, and poor fetal outcomes have to be carefully weighed (10).

We advise patients that pregnancy post-transplantation carries increased risks of hypertension, preeclampsia, preterm birth, low birth weight, and cesarean section. Babies are born at a lower gestational age and a lower mean birth weight (4–6). Risk of birth defects is comparable with the general population (4.5% versus 3%–5%) (4). We also discuss the implications of low birth weight and prematurity on risk for poorer health in adulthood.

Patients are seen at 1–2 monthly intervals and referred to a high-risk obstetrics clinic. We perform laboratory work to follow kidney function and drug levels every 4 weeks in early pregnancy, increasing in frequency to every 2 weeks in the second and third trimesters. Patients with complications and poorer kidney function are seen more frequently (8–10).

“Can I Take My Usual Medications?”

Review of Potentially Teratogenic Medications

Medications should be reviewed by experienced care providers for safety. Many medications are not licensed in pregnancy although the federal drug administration grants letter grades to medications which may be used (grades A, B, and C) and drugs considered unsafe (grades D and X). An updated classification, the Pregnancy and Lactation Final Rule, was issued in 2015.

Immunosuppression

The calcineurin inhibitors, cyclosporine and tacrolimus have been linked to fetal growth retardation and preterm delivery, but are generally felt to be safe, consistent with the Pregnancy and Lactation Final Rule recommendations. MMF is a teratogen and is substituted with azathioprine at least 6 weeks before attempting pregnancy. There is limited evidence of safety for the mammalian target of rapamycin inhibitors and belatacept and we avoid these drugs. Prednisone is considered safe in pregnancy (8).

As a result of changes in GFR and drug metabolism, drug levels can vary during pregnancy. To maintain whole blood drug levels of tacrolimus in their prepregnancy range typically necessitates a 20%–25% increase in total dose.

“Will I and My Kidney Be OK?”

Changes in Kidney Function

There is a physiologic increase in GFR beginning in the first trimester by up to 40% and this is sustained throughout pregnancy and early postpartum. Absence of this increase in GFR in early pregnancy portends a poor prognosis. There is also an increase in proteinuria, with most obstetrics guidelines accepting a cutoff of 300 mg/d.

Changes in BP

In normal pregnancy, systemic BP falls in response to hormonal changes. Preeclampsia may be difficult to diagnose in women with preexisting hypertension and proteinuria. Uterine Doppler with fetal assessments may be helpful. On the basis of findings from the CHIPS trial, the Italian Society of Nephrology position statement suggests a BP goal of <130/80 mm Hg and an acceptable BP as being <140/90 mm Hg (10,11). Agents such as labetalol, methyldopa, and the calcium channel antagonists are first-line choices and care should be taken to avoid potentially teratogenic drugs. Addition of low-dose aspirin reduces risk of gestational hypertension and preeclampsia.

Graft Loss in Pregnancy

There should be a low threshold for suspecting allograft dysfunction. As creatinine normally falls in pregnancy because of an increase in GFR, even a small rise in serum creatinine may portend a significant degree of kidney injury. Acute rejection rates vary in reports but are likely similar to that in the general transplant population. Rates of graft loss at 2 years post-transplant vary from 5% to 9% (4–6).

“Will I Need a Cesarean Section, and Can I Breastfeed?”

The kidney allograft does not affect normal vaginal delivery and a cesarean section is not routinely indicated. In the event of surgery, care should be taken to avoid injury to the ureter of the kidney allograft, which may be anterior to the uterine artery.

Breast feeding is recommended by the American Association of Pediatrics for the first 6 months of life and this practice is not opposed by the American Society of Transplantation. The online LACTMED database maintained by the National Institutes of Health is a helpful resource on the safety of drugs during breast feeding. Although low levels of drug and drug metabolites can be detected in breast milk, a regimen of tacrolimus, azathioprine and prednisone is felt to be safe (8).

Follow-Up of Our Patient

Our patient did not wish to delay pregnancy. After extensive counseling, we collaborated with her to optimize her pregnancy outcome. MMF was switched to azathioprine. Aspirin 81 mg daily was started. Trimethoprim-sulfamethoxazole and atorvastatin were stopped. She became pregnant at about 10 months post-transplant. Her BP remained well controlled without medications. Although there was a small increase in proteinuria to 0.5 g/g, her serum creatinine improved from 1.0 to 0.8 mg/dl. She was induced at 36 weeks of gestation because of an abrupt rise in serum creatinine, and had a cesarean section delivery for a nonreassuring fetal heart rate. Her baby was healthy but of low birth weight. She elected not to breast feed. Her creatinine returned to baseline postdelivery and has remained stable 2 years post-transplant.

Disclosures

Dr. Kumar reports receiving honorarium from the American Society of Nephrology, the American Society of Nephrology-American Society of Transplantation, and Mallinckrodt outside the submitted work. Dr. Ong has nothing to disclose.

Funding

Dr. Kumar received grants from National Institutes of Health Clinical Trials in Organ Transplantation.