Immunosuppression in Uterus Transplantation: Experience From the Dallas Uterus Transplant Study : Transplantation

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Original Clinical Science—General

Immunosuppression in Uterus Transplantation: Experience From the Dallas Uterus Transplant Study

Wilson, Nicole K. PharmD, MSc1; Schulz, Philipp MD2; Wall, Anji MD, PhD2; Parrott, Megan MD2; Testa, Giuliano MD, MBA2; Johannesson, Liza MD, PhD2,3; Sam, Teena PharmD, BCCP1

Author Information
Transplantation: November 22, 2022 - Volume - Issue - 10.1097/TP.0000000000004437
doi: 10.1097/TP.0000000000004437
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Abstract

INTRODUCTION

Uterus transplantation (UTx) is an emerging treatment for absolute uterine factor infertility, with the first successful live birth occurring in the US in 2017.1 The majority of women who undergo UTx have Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, which is characterized by the congenital absence of the uterus. UTx is a temporary transplant that offers women with absolute uterine factor infertility the option of achieving pregnancy and childbirth followed by graft hysterectomy. The unique features of UTx require special considerations regarding immunosuppression (IS) and monitoring compared with other solid organ transplants. First, the IS agents used must be safe during pregnancy. Second, UTx recipients are generally young and healthy and may need different IS regimens than chronically ill solid organ transplant recipients to prevent rejection. Third, special attention must be paid to renal function in this population given the elective nature of the procedure, the long posttransplant life expectancy, and the association of MRKH with concurrent kidney malformation.2-4 Finally, acute cellular rejection (ACR) in UTx is largely subclinical and currently requires protocol biopsies for early diagnosis.5

The safety profile of IS agents is paramount in UTx. The US Food and Drug Administration publishes pregnancy considerations for all drugs. Minimal data on pregnancy are available for several IS agents: calcineurin inhibitors such as tacrolimus; mammalian target of rapamycin inhibitors,6 for example, sirolimus and everolimus (EVR)7; azathioprine (AZA)8,9; and glucocorticoids.10 The possibility of fetal harm cannot be ruled out for these agents, but they can generally be considered safe at therapeutic doses during pregnancy, and similar maternal–fetal outcomes have been shown in solid organ transplant recipients compared with nontransplant patients.7 Mycophenolic acid (MPA) is an IS drug that poses a fetotoxic profile and has been associated with higher rates of abortion and congenital malformations.11-15

In a recent review summarizing 45 UTx recipients’ IS regimens,16 most recipients received tacrolimus-based maintenance IS (43/45, 96%) in combination with mycophenolate mofetil (33/45, 73%) immediately postoperatively. Regimens used in anticipation of embryo transfer were reported in 29 of 45 recipients, all of whom were maintained on tacrolimus. Fifteen of these 29 were on tacrolimus monotherapy (52%), 11 (38%) were on dual therapy with tacrolimus and AZA, and 2 (7%) were on triple therapy with tacrolimus, AZA, and corticosteroids. EVR was used in combination with tacrolimus immediately postoperatively in 3 cases (3/45, 7%) and in anticipation of embryo transfer in 1 case (1/29, 3%). ACR, defined by histological findings, clinical findings, or an elevated CD4/CD8 ratio, was reported in 46% of UTx recipients. The majority (92%) of rejection episodes were diagnosed histologically, of which 63% were categorized as grade 1 (mild). One case of severe ACR (grade 3) was successfully treated with intravenous corticosteroids, whereas 2 other cases were resolved with additional rabbit antithymocyte globulin (rATG; Thymoglobulin, Genzyme Corporation).16

Despite this report, questions remain regarding the optimal IS regimen required to prevent rejection while minimizing toxicity to the UTx recipient and fetus. As the goal of IS in solid organ transplant recipients shifts to incorporate patient-reported outcomes instead of focusing solely on preventing rejection, graft loss, and mortality,17 we aim to share our recipients’ experiences with tolerability and adverse events related to IS agents. This study provides a detailed report of IS therapy—including infection, rejection, donor-specific antibody (DSA) development, renal function, maternal and fetal complications, tacrolimus troughs, and the use of extended-release tacrolimus—at our center, which represents the largest cohort of UTx cases worldwide.

MATERIALS AND METHODS

DUETS (Dallas UtErus Transplant Study) was initiated in November 2015. The study received research approval through the Baylor University Medical Center ethics committee and institutional review board and is registered on ClinicalTrials.gov (NCT02656550). All participants provided written informed consent to participate and for preoperative and postoperative data collection.

Outcome Measures

Outcomes measured included tacrolimus trough levels before, during, and after any pregnancy; treated episodes of ACR; DSA formation; serum creatinine (pretransplant, maximum while nonpregnant, maximum while pregnant, and posthysterectomy); incidences of infection, adverse drug effects, maternal medical complications, rejection episodes, live births, and miscarriages; and recipient-graft time, defined as time from UTx to graft hysterectomy.

Immunosuppression Protocol

All recipients received induction with rATG (4.5 mg/kg in 3 divided doses) and methylprednisolone 1000 mg at the time of transplantation. A corticosteroid taper was utilized in the first 4 recipients to include prednisone 15 mg/d by posttransplant day 7, then the dose was decreased by 2.5 mg/d weekly until it was discontinued on posttransplant day 42. To reduce overall maintenance IS exposure, the remaining 10 recipients did not receive corticosteroids postoperatively.

Maintenance IS was achieved with oral tacrolimus initiated at 0.05 mg/kg of the immediate-release formulation (IR-Tac) every 12 h, which was converted to extended-release (XR-Tac) once a stable dose was established. Targeted tacrolimus trough levels were 8–10 ng/mL during months 1–3 posttransplant; 5–8 ng/mL during months 4–6; 5–6 ng/mL during months 7–12; and 3–5 ng/mL after the first year posttransplant (Table 1). Tacrolimus trough targets were not altered during pregnancy. We monitored drug levels at 1- to 2-wk intervals after UTx and throughout pregnancy. MPA was used for cases 4, 5, 6, and 7, and embryo transfer was performed after a 3-mo washout. MPA was replaced after the ninth recipient with AZA or EVR, which allowed us to consider earlier embryo transfer as soon as 3 mo after induction therapy.18,19 All recipients received low-dose aspirin (81 mg) daily from UTx throughout pregnancy and the postpartum period.

TABLE 1. - Overview of induction and maintenance immunosuppression and rejection therapy for uterus transplantation in the Dallas UtErus Transplant Study (DUETS) cohort
Type Agent Details
Induction Rabbit antithymocyteglobulin 4.5 mg/kg IBW (3 divided doses at the time of UTx and until posttransplant day 5 based on lab results)
Methylprednisolone 1000 mg at the time of UTx
Maintenance Tacrolimus  0.5 mg/kg IBW initiation dose
 Targeted trough levels after UTx:
  Months 1–3: 10ng/mL
  Months 4–6: 5–8ng/mL
  Months 7–12: 5–6ng/mL
  Months >12: 3–5 ng/mL
Azathioprine 1 mg/kg (approximately 50–75 mg)
Everolimus(if azathioprine is not tolerated)  0.75 mg twice a day
 Targeted trough levels after UTx:
  Months 1–3: 3–8 ng/mL
  Months ≥4: 3–8 ng/mL
Therapy forrejection Methylprednisolone Day 1: 1000mg
Day 2: 500 mg
Day 3: 500 mg
Refractory rejection:Rabbit antithymocyte globulin 4.5 mg/kg IBW (3 divided doses)
IBW, ideal body weight; UTx, uterus transplantation.

Rejection episodes were treated with intravenous methylprednisolone 1000 mg on day 1 and 500 mg on days 2 and 3. A repeat cervical biopsy was done 1 wk after rejection treatment.

Acute Cellular Rejection Monitoring

Ectocervical biopsies were collected per protocol given the asymptomatic nature of ACR in the UTx allograft. Ectocervical biopsy collection occurred on postoperative day 5 (±2 d), every week until 4 wk, every 4 wk before and after pregnancy, and once every trimester during pregnancy. Biopsies were graded as negative for ACR, borderline, or grades 1–3.5 Human leukocyte antigen-antibody testing was performed during pretransplant evaluation, at the time of transplant, and concurrently with every cervical biopsy. DSA for human leukocyte antigen was identified using single antigen beads (One Lambda Inc, Canoga Park, CA) and Luminex 3D instruments (Luminex Corp, Austin, TX) with a positive cut-off of ≥1000 mean fluorescence intensity. We monitored borderline to mild rejection episodes and initiated corticosteroid treatment only for moderate to severe cases.5

Data Analysis

Study data were collected and managed using REDCap electronic data.20,21 Descriptive statistics were used for data reporting. Continuous variables were reported using medians ± SDs and the interquartile range (IQR), and categorical variables as absolute counts and percentages out of the total nonmissing within each variable.

RESULTS

Twenty patients underwent UTx at Baylor University Medical Center in Dallas from September 2016 to August 2019. The 14 recipients who had a viable uterine graft 30 d after UTx were included in this study. Six recipients experienced graft loss within 30 d of transplant, attributed to vascular complications, graft selection, and one case of postoperative hemorrhage, the details of which are described elsewhere.22 The median recipient age at UTx was 31 y (range, 20–35), and most were Caucasian (n = 12, 86%). The indication for UTx was absolute uterine-factor infertility in all cases, with 13 (93%) diagnosed with congenital agenesis of the uterus (MRKH). One recipient (7%) had undergone a previous hysterectomy due to unresectable myomas. One recipient (7%, case 9) had a solitary kidney. There were 14 live births from this cohort, with 2 recipients experiencing 2 live births each and 10 recipients having 1 live birth. The 2 recipients who have not experienced live birth at the time of this publication are in the process of embryo transfer after having experienced miscarriages. The majority (n = 13, 93%) of the donors were living (Table 2). At the time of this publication, 11 recipients had undergone graft hysterectomies. The median graft time in those who underwent graft hysterectomy was 604 d (IQR 422, 860 d).

TABLE 2. - Demographic characteristics and outcomes of uterus transplant recipients
Variable All (N = 14)
Age at UTx, median (range), y 31 (20–35)
Race, n (%) Caucasian 12 (86)
Asian 1 (7)
African American 1 (7)
Body mass index, median (IQR), kg/m2 24 (22–29)
Donor type, living, n (%) 13 (93)
Uterus explanted postpartum, n (%) 11 (79)
Median graft time, median (IQR), days 604 (442–860)
Live births, n 0 2
1 12
2 2
Miscarriages, n 0 9
1 2
2 1
3 1
Total 7
DSA development, n (%) 2 (14)
Rejections, n 0 4
1 6
2 2
3 2
Total 16
Rejection episodes per recipient 1.14
Infections, n 0 7
1 3
2 4
Total 11
Infection episodes per recipient 0.79
Side effects immunosuppression, n 8
Maternal medical complications, n 4
DSA, donor-specific antibody; IQR, interquartile range; UTx, uterus transplantation.

Immunosuppression

rATG and methylprednisolone were given to all recipients at the time of UTx per protocol. No adjustments to rATG dosing or steroid dosing were required.

All recipients were maintained on tacrolimus for the duration of the recipient-graft time. Twelve recipients (86%) were maintained on XR-Tac (Envarsus XR, Veloxis Pharmaceuticals). Conversion to XR-Tac occurred in 2 recipients before hospital discharge and before 3 mo in 10 recipients. Two recipients (cases 6 and 20) on XR-Tac were later converted to IR-Tac due to concern for trough variability, one case of which was thought to provoke a moderate (grade 2) ACR (Table 3).

TABLE 3. - Immunosuppression regimen and adverse events per uterus transplant recipient
Case Initial regimen (at discharge) Regimen, 3-mo PT Regimen, 1-y PT Type of infection Side effects of immunosuppression Maternal medical complications Rejection DSA formation
4 IR-Tac + MPA + CS taper IR-Tac + MPA IR-Tac + AZA #1 UTI, a day 12#2 UTI, c day 239 NT, b day 183 #1 Day 155: MP 2.5 g
5 XR-Tac + MPA + CS taper XR-Tac + MPA XR-Tac + AZA #1 UTI, d day 211#2 Sinus infection, e day 547 #1 Day 547: MP 2.5 g#2 Day 616: MP 1.5 g
6 IR-Tac + MPA + CS taper XR-Tac + AZA IR-Tac + AZA Cervicitis, f day 6 NT, g day 13 GHTN, h day 910 #1 Day 330: MP 2.5 g
7 IR-Tac + MPA + CS taper IR-Tac + AZA XR-Tac + AZA GDM, i day 691
9 IR-Tac + EVR XR-Tac + EVR XR-Tac + AZA UTI, j day 422 NT, k day 555
11 XR-Tac + AZA XR-Tac + AZA XR-Tac + AZA #1 Mastitis, l day 403#2 Sinus infection, m day 753 #1 Day 104: MP 2.5 g
12 IR-Tac + AZA XR-Tac + AZA XR-Tac + AZA #1 Day 22: MP 1.5 g#2 Day 1012: MP 2.5 g #1 Day 28 n #2 Day 266 o #3 Day 231 p #4 Day 423 q
13 IR-Tac + AZA XR-Tac + AZA XR-Tac + AZA #1 Day 17: MP 2.5 g + taper
15 IR-Tac + AZA IR-Tac + EVR IR-Tac + EVR #1 N/V, r day 3#2 NT, r day 635 Day 442, preeclampsia s #1 Day 29: MP 2 g#2 Day 511: MP 2 g#3 Day 588: MP 2.5 g, rATG 4.5 mg/kg IBW
16 IR-Tac + AZA XR-Tac + AZA XR-Tac + AZA Day 265, GHTN t
17 IR-Tac + AZA XR-Tac + AZA XR-Tac + AZA
18 IR-Tac + AZA XR-Tac + AZA XR-Tac + AZA #1 UTI, u day 407#2 Incisional erythema, w day 453 Diarrhea, v day 13 #1 Day 92: MP 1.5 g + taper
19 IR-Tac + AZA XR-Tac + AZA XR-Tac + CS CMV viremia, x day 144 #1 HT, y day 11#2 NT, y day 594 #1 Day 509: MP 2 g
20 IR-Tac + AZA XR-Tac + AZA IR-Tac + AZA + CS #1 Day 19: MP 3.5 g#2 Day 38: MP 1 g#3 Day 214: MP 4.5 g + taper Day 18 z
aTreatment with ciprofloxacin for 10 d.
bTacrolimus dosage reduced.
cTreatment with ciprofloxacin for 5 d.
dTreatment with nitrofurantoin for 5 d and amoxicillin for 4 d.
eTreatment with amoxicillin for 4 d.
fTreatment with ciprofloxacin for 4 d.
gIntermittent-elevated serum creatinine level; tacrolimus dosage reduced.
hRecipient suffered from prepregnancy hypertension, which was not treated; treatment was started with nifedipine at GW 17.
iOccurrence GW 26; treatment with metformin and insulin.
jTreatment with nitrofurantoin for 7 d.
kPersistent low elevation in serum creatinine from time of starting immunosuppression.
lTreatment with cefalexin for 7 d.
mTreatment with amoxicillin for 8 d.
nDQ7 at 1000–6000 MFI; not noted after day 392.
oDR52 at 1000 MFI, not noted after day 454.
pDRB3*02:02 at 2000 MFI.
qB8 at 1000 MFI.
rN/V: Switch to everolimus; immunosuppression discontinued due to NT based on laboratory trends and kidney ultrasound showing parenchymal disease.
sOccurrence GW 36 6/7; delivery of newborn.
tOccurrence GW 15; treatment with nifedipine.
uAntibiotic treatment was denied by the recipient.
vSwitch to XR-Tac (Envarsus).
wTreatment with cefalexin for 7 d.
xCMV donor positive/recipient negative. Initial prophylaxis: oral valganciclovir 450 mg daily for 3 mo; Treatment: ganciclovir 5 mg/kg twice daily intravenously for 3 wk; second prophylaxis: oral valganciclovir 450 mg twice daily for 2 mo.
yElevated liver enzymes, which were monitored and normalized without any interventions after 32 d; decreasing renal function and acute kidney injury – immunosuppression discontinued and hysterectomy.
zDR53 at 1000 MFI noted once; not seen again in future samples.
AZA, azathioprine; CMV, cytomegalovirus; CS, corticosteroid; day, days after transplantation; DSA, donor-specific antibody; EVR, everolimus; GDM, gestational diabetes mellitus; GHTN, gestational hypertension; GW, gestational week; HT, hepatotoxicity; IBW, ideal body weight; IR-Tac, immediate-release tacrolimus (Prograf); MP, methylprednisolone; MPA, mycophenolic acid; NT, nephrotoxicity; N/V, nausea/vomiting; PT, posttransplant; rATG, rabbit antithymocyte globulin; UTI, urinary tract infection; XR-Tac, extended-release tacrolimus (Envarsus).

Trough levels were highest in the early posttransplant period, with a median of 8.6 ng/mL (IQR 6.6, 11.6 ng/mL). During pregnancy, trough levels were lower, with a median of 6.3 ng/mL (IQR 4.9, 8 ng/mL). Postpregnancy trough levels were a median of 7.0 (IQR 5.3, 8.775). Neonatal tacrolimus levels have been reported previously and were noted to decrease by day of life 5.23

The majority of recipients (n = 9, 64%) received AZA 1 mg/kg (rounded to the nearest 25 mg) as the second agent together with tacrolimus before hospital discharge. Five recipients were started on another agent and later converted to AZA. Of these 5, 4 were started on MPA immediately posttransplant and converted to AZA after 187, 114, 70, and 42 d (cases 4, 5, 6, and 7, respectively), and 1 (case 9) was started on EVR immediately postoperatively and converted to AZA after 289 d.

In 2 recipients who were started on AZA as a second agent, the medication was either temporarily or permanently ceased. In 1 recipient (case 15), AZA was replaced with EVR on posttransplant day 38 due to loss of appetite and weight loss, which improved upon conversion. In the other recipient (case 19), AZA was held, and prednisone 5 mg daily was initiated on posttransplant day 147 in response to cytomegalovirus viremia.24 During her pregnancy, she received XR-Tac and corticosteroids. AZA was later reinitiated due to a rejection episode. The recipient was maintained on tacrolimus, AZA, and prednisone until discontinuation of IS.

Acute Cellular Rejection

A total of 16 ACR episodes requiring treatment occurred in 10 recipients (Table 4). Total doses of methylprednisolone for rejection treatment ranged from 1.5 to 4.5 g divided over 3 d (Table 3). One case of steroid-refractory rejection occurred in case 15 after her first pregnancy. Most rejection episodes (n = 8, 50%) occurred within the first 6 mo posttransplant and outside of any pregnancy. Only one rejection episode occurred during pregnancy (case 20, gestational week [GW] 12), which responded to steroids.

TABLE 4. - Characteristics of uterus transplant recipient with and without rejection
Rejection (n = 10) No rejection (n = 4) P
Age at UTx, median (range), y 31 (28–34) 28 (24–34) NS
Race, n (%) NS
 African American 0 (0) 1 (25)
 Asian 1 (10) 1 (25)
 Caucasian 9 (90) 2 (50)
Donor type, living, n (%) 9 (90) 4 (100) NS
Uterus explanted postpartum, n (%) 8 (80) 3 (75) NS
Number of live births, n (%) NS
 0 1 (10) 1 (25)
 1 7 (70) 3 (75)
 2 2 (20) 0 (0)
Number of miscarriages, n (%) NS
 0 7 (70) 3 (75)
 1 2 (20) 0 (0)
 2 1 (10) 0 (0)
 3 0 (0) 1 (25)
 Total 4 3
DSA development on IS, n (%) 2 (20) 0 (0) NS
Number of infections, n (%) NS
 0 4 (40) 3 (75)
 1 2 (20) 1 (25)
 2 4 (40) 0 (0)
 Total 10 1
Side effects immunosuppression, n (%) 7 (70) 1 (25) 0.07
Maternal medical complications, n (%) 2 (20) 2 (50) NS
P > 0.2 were denoted as NS.
DSA, donor-specific antibody; IS, immunosuppression; NS, not significant; UTx, uterus transplantation.

Donor-specific Antibody Development

DSA development while on IS was observed in 2 recipients (Table 3). No cases of DSA were thought to have caused graft injury on biopsy. IS was discontinued at the time of graft hysterectomy in 6 of the 11 recipients who had undergone graft hysterectomy at the time of this report. In 5 recipients, IS was discontinued in anticipation of graft hysterectomy (median 53 d prior; IQR 49, 81).

DSA monitoring continued after discontinuation of IS or hysterectomy, and all recipients ultimately developed human leukocyte antigen antibodies to the uterus donor without IS, despite hysterectomy. In those who had IS discontinued at the time of graft hysterectomy, time to DSA development after IS discontinuation was 62 d [IQR 39, 85], compared with 64 d [IQR 47, 94] in those who discontinued IS before graft hysterectomy. At the time of the latest follow-up (median 452 d after IS discontinuation; IQR 322, 730; and median 392 d after graft hysterectomy; IQR 274, 729), all 11 recipients had persistent DSA. Median number of DSA per recipient was 3 (IQR 2, 4) to class I human leukocyte antigen alleles and 3 (IQR 3, 5) to class II. Mean fluorescence intensity (MFI) of the immunodominant DSA at the time of latest follow-up was median 25 000 (IQR 16 000, 27 000). No difference in the development of DSA or symptomatic rejection was observed whether IS was discontinued before or at the time of graft hysterectomy.

Renal Function

Before the transplant, the recipients’ median serum creatinine was 0.76 mg/dL (n = 14; IQR 0.68, 0.84 mg/dL). The median peak value was 1.05 mg/dL (n = 14; IQR 0.88, 1.36 mg/dL) outside of pregnancy and 1.04 mg/dL (n = 12; IQR 0.84, 1.36 mg/dL) during pregnancy. At 6 mo posthysterectomy, the median serum creatinine was 0.86 mg/dL (n = 9; IQR 0.66, 0.95 mg/dL).

Infection

There were 11 episodes of infection in 7 recipients while receiving IS therapy (Table 3). We identified 5 episodes of urinary tract infections in 4 recipients, which were resolved with antibiotics. One case presented with recurrent incisional erythema (case 18), which was treated with antimicrobial treatment. Another recipient had cytomegalovirus viremia, which was previously reported in detail.24 Two episodes of sinus infection and 1 case each of mastitis and cervicitis were successfully treated with antibiotics.

Adverse Effects of Immunosuppression

Renal Complications

We identified 8 episodes of adverse effects associated with the use of IS agents in 6 of our recipients. Five UTx recipients (cases 4, 6, 9, 15, and 19) had acute kidney injury as documented by the treating physician. One recipient (case 4) had elevated prepregnancy serum creatinine levels, which were above median value throughout pregnancy (1.1–1.4 mg/dL). The tacrolimus dosage was reduced in this case, but the recipient had a premature delivery at GW 33 1/7 owing to acute kidney injury attributed to exposure to tacrolimus. Case 6 showed intermittent elevated serum creatinine levels; therefore, we lowered the tacrolimus dosage and she had a planned delivery at GW 38. Case 9, who had only 1 kidney, experienced marginally elevated serum creatinine levels from the time of starting on IS therapy. In addition to tacrolimus, she was on EVR immediately postoperatively, which was later converted to AZA. She had preterm labor at GW 30 6/7, and it was decided to perform a hysterectomy after the postpartum period to protect her remaining kidney function. Case 15 was diagnosed with nonsevere preeclampsia at GW 36 6/7, and immediate delivery was performed. Creatinine levels remained marginally elevated, and a 6-mo postpartum renal ultrasound showed a slight interval decrease in renal size, with parenchymal findings suggestive of nonspecific parenchymal disease. The decision was made to discontinue IS therapy 6 mo postpartum, and a hysterectomy was performed. Creatinine returned to baseline posthysterectomy and has remained stable for up to 2 y. Another recipient (case 19) developed acute kidney injury in the last 3 mo of her pregnancy that did not improve postpartum. Thus, IS agents were discontinued 6 mo after the first delivery, and she underwent graft hysterectomy 3 mo later. Her creatinine has remained stable posthysterectomy.

Gastrointestinal Complications

Case 15 complained of severe nausea and vomiting while receiving AZA. She was switched to EVR, which improved her symptoms. Case 18 had persistent diarrhea when she was on IR-Tac; she was switched to XR-Tac with resolution of her symptoms. Elevated liver enzymes were detected in case 19 and normalized without intervention after 1 mo.

Maternal Medical Complications

Maternal medical complications in our cohort have been previously reported.25,26 One recipient (case 6) had prepregnancy hypertension but required no medication at that time.Because she showed frequent hypertensive episodes, antihypertensive therapy was started at GW 17. Case 7 was diagnosed with gestational diabetes, which was detected at GW 26. Therapy was started with diet changes and metformin, but she was later converted to insulin because of side effects from metformin. One case (7%) of preeclampsia occurred in case 15, which required delivery of the newborn at 36 6/7 wk. Another recipient (case 16) developed gestational hypertension at GW 15, which was treated with nifedipine and remained stable. Some of the aforementioned complications may have been exacerbated by metabolic components, given body mass index calculations of 31, 29, and 29 in cases 7, 15, and 16, respectively, at the time of study enrollment.

DISCUSSION

This is the first detailed report of IS management in the largest cohort of UTx recipients. Induction therapy consisted of rATG and was given in all our cases before transplantation and was additionally required in 1 case of refractory rejection (case 15). Thymoglobulin labeling reports an unknown risk of fetal harm and recommends use only when the benefits outweigh the risk. Nonetheless, the administration of rATG (with or without methylprednisolone) as induction therapy or rejection treatment was given in most cases of UTx16 and appears to be safe and appropriate.

Maintenance therapy was primarily achieved in our UTx recipients with tacrolimus. Tacrolimus can be given as XR-Tac or IR-Tac. Proposed benefits of XR-Tac are a more favorable pharmacokinetic profile with reduced peak tacrolimus concentrations, allowing the potential for reduced toxicity and improved medication adherence is given that it is a once-daily dose compared with IR-Tac.27,28 The dosage of tacrolimus was gradually reduced and kept at the target trough in recipients during pregnancy. Despite the lower levels, we only experienced 1 episode of rejection during pregnancy (case 20, GW 12), which was responsive to steroids. Tacrolimus trough levels were higher than the trough target of 3–5 ng/mL after the first year posttransplant, with a median of 7.0 (IQR 5.3, 8.78). Our experience provides clinical evidence of XR-Tac efficacy during pregnancy and in UTx recipients. The pharmacokinetics of IR-Tac are known to vary in pregnant compared with nonpregnant patients,29 whereas the effects of pregnancy on XR-Tac pharmacokinetics have not yet been investigated.

MPA is commonly used for maintenance IS in solid organ transplant recipients. Several congenital malformations and obstetric complications have been reported with its use.12-15,30,31 Following early UTx protocols, MPA was given to the first 4 UTx recipients in our cohort and stopped 10 to 16 wk before ET. We did not find any fetal malformations, and all infants were appropriate size for gestational age23 in our recipients who temporarily received MPA. However, we replaced MPA with AZA or EVR. AZA (n = 9, 64%) or EVR (n = 1, 7%) was the initial maintenance therapy, or recipients were later converted to AZA. Early conversion or de novo use of these agents allows for earlier embryo transfer than those maintained on MPA, which reduces cumulative IS exposure.19 AZA is considered a safe drug in pregnant organ transplant recipients and is not associated with a higher rate of congenital malformations.32,33 Data on the use of EVR in transplant recipients throughout pregnancy are scarce; however, the few cases published did not report any complications in mothers or their newborns.34-37

IS agents increase the risk of infection. Infection-related mortality has declined over the past decade but still accounts for 13% of deaths and 8% of death-censored graft failure in kidney transplant recipients.38,39 The reported infectious episodes per patient range from 0.98 in kidney transplant recipients to 3.19 in heart-lung transplant recipients.40 The infectious etiology depends on the time of its occurrence. Infections in the first 6 mo are associated with transplantation, whereas infections afterward mirror those in the general population.41-43 We identified 11 infections in our 14 recipients (infection episodes per patient, 0.79) while receiving IS. Most infections in our cohort (n = 8, 73%) were diagnosed beyond 6 mo posttransplantation and were of bacterial origin (n = 10, 91%). Considering these results, we believe that our IS regimen depicts a well-balanced combination without increased susceptibility to infection.

Maternal medical complications such as preeclampsia occur among 21% of kidney transplant recipients,44 whereas patients suffering from unilateral renal agenesis have a higher risk of up to 75%.16 In our cohort, there was 1 case (7%) of preeclampsia in case 15, requiring delivery at GW 36 6/7. This recipient did not have any renal abnormalities. So far, 2 other cases of preeclampsia in UTx recipients, who each had a single kidney, were reported in UTx pregnancies and warranted preterm delivery.26 In our cohort, the rate of gestational hypertension was 14%, which is less than observed in pregnant kidney transplant recipients.44 The rate of gestational diabetes in our population was similar to that of pregnant kidney transplant recipients at 7%.44

One concern in this population remains renal toxicity of calcineurin inhibitors, especially because most recipients have MRKH syndrome with associated renal abnormalities.45,46 In 5 recipients (cases 4, 6, 15, 9, and 19), we decided to proceed with a graft hysterectomy after the first pregnancy for renal protection owing to persistently elevated serum creatinine levels. An alternative solution may have been conversion to belatacept, a selective T-cell co-stimulation blocker, which does not carry the risks of nephrotoxicity.47 However, safety data on belatacept in pregnancy are extremely limited, and additional data to support its use are needed.48

Sensitization to HLA following uterus transplant has not been previously described. In our cohort, after graft hysterectomy recipients developed multiple, persistent DSAs. Similar phenomenon has been described after a kidney transplant nephrectomy.49,50 Although a graft hysterectomy removes the whole uterus and cervix, the vasculature is not dissected entirely to the external iliac. Thus, it is possible that remnants of donor tissue remain posthysterectomy, which could also invoke DSA development. Although long-term renal dysfunction has not been a concern to date in our population, this could have important implications on access to kidney transplants if renal failure were to develop post-uterus transplant in this young cohort. Our approach of discontinuing IS in anticipation of graft hysterectomy in select patients (n = 5; median 53 d prior; IQR 49, 81) did not impact the development of DSA or symptomatic rejection, and may be considered in cases in which the risks of continued IS agent use outweigh the benefits.

The aim of IS therapy in UTx is to ensure graft survival by preventing rejection while minimizing teratogenic risks to the fetus and adverse effects in UTx recipients. To date, all babies born to mothers in the DUETS trial were born healthy with no developmental abnormalities or significant toxicities related to IS use. In UTx recipients, induction therapy with rATG with dual maintenance therapy of tacrolimus and de novo AZA depicts a well-tolerated IS regimen that allows a short time for embryo transfer. The incidence of rejection during pregnancy in other types of organ transplantation ranges from 4% to 5%.44 All rejections in our cohort were clinically silent and responded well to methylprednisolone or rATG treatment. The rate of ACR in our cohort was similar to ACR during pregnancy in other solid organ transplant recipients. In our practice, ectocervical biopsy monitoring is required to detect clinically silent rejection. The use of donor-derived cell-free DNA may present an alternative to ectocervical biopsy monitoring, and further research is needed in this area. Despite pregnancy being an immunologically sensitizing event, DSA occurrence was infrequent while on IS. Two recipients (cases 12 and 20) developed transient, low-level DSA while on IS, and all recipients developed DSA once IS was discontinued, suggesting that the degree of IS therapy in our recipients during the study period was adequate.

CONCLUSION

IS for UTx must be tailored to healthy recipients who desire pregnancy. Maternal and obstetric complications due to IS therapy can occur and must be carefully monitored in UTx recipients, especially those with renal anomalies. Our experience demonstrates that in UTx recipients an IS regimen of XR-Tac or IR-Tac, with trough targets of 6–8 ng/mL, and AZA 1 mg/kg daily can safely be used to prevent graft loss and minimize toxicity along with protocol ectocervical biopsy rejection monitoring. Rejection episodes are largely steroid responsive, and medication side effects are manageable with changes to IS regimens while safely navigating pregnancy and delivery.

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