Abstract
Background:
Infertility is common among those with kidney transplants, and pregnancy is associated with high risk of adverse maternal and fetal outcomes. Little is known about the outcomes of pregnancy with assisted reproductive technology in women with kidney transplants.
Methods:
This retrospective cohort study used data from the Transplant Pregnancy Registry International. Eligible participants were recipients of a kidney transplant between March 1968 and July 2022 who were aged 14 years or older at conception. Logistic regression analyses (adjusted for age at conception and race) were constructed to compare pregnancy outcomes with assisted reproductive technology versus natural conception.
Results:
There were 130 pregnancies utilizing assisted reproductive technology (ART) in 77 kidney transplant recipients. ART pregnancies, as compared to natural conception pregnancies, were associated with higher adjusted likelihood of hypertension during pregnancy (OR, 1.57; CI, 1.06–2.32), higher adjusted likelihood of cesarean delivery (OR, 1.60; CI, 1.02–2.51), and higher adjusted risk of preterm births <37 weeks. (OR, 2.07; CI, 1.35–3.18). Pregnancies with ART, as compared to natural conception, had a lower median birth weight (2551 grams vs. 2722.0 grams), a lower median gestational age (36.0 weeks vs. 37.0 weeks), and higher proportion of neonatal deaths (4.4% vs. 0.8%). There were no differences in the adjusted likelihood of preeclampsia, gestational diabetes, miscarriages, live births, low birth weights, birth defects, or 2-year graft loss between ART vs. natural conception pregnancies.
Conclusion:
ART pregnancies are associated with higher risk of preterm births, hypertension during pregnancy, and cesarean delivery compared to naturally conceived pregnancies. The likelihood of live births and 2-year graft loss did not differ.
Keywords: Assisted Reproductive Technology, In-vitro Fertilization, Hypertension, Live Births, Kidney Transplant
Lay Summary
Little information is available regarding pregnancy outcomes with assisted reproductive technology in women with kidney transplants. Among kidney transplant recipients, pregnancy with assisted reproductive technology increases the risk of preterm births, hypertension during pregnancy, and cesarean delivery compared to natural conception. There is no difference in the rate of 2-year graft loss and live births. This knowledge can help physicians and patients with kidney transplant in preconception planning with assisted reproductive technology.
Introduction
Childbearing is an integral part of many women with kidney transplants. There is disruption of the hypothalamic-gonadal axis, anovulation, and impaired fertility with chronic kidney disease.1 However, a kidney transplant offers the best hope to women with advanced kidney disease who wish to become pregnant.2 There is rapid restoration of the hypothalamic gonadal axis with the return of circulating sex hormones to normal range as soon as six months after receiving a kidney transplant. Thousands of successful pregnancies have occurred since the first reported successful pregnancy after a kidney transplant in 1958.3,4
Most women with kidney transplants conceive naturally, but few women with persistent infertility may need assisted reproductive technology for conception. The use of assisted reproductive technology has increased since the 1980s; the first reported live birth following in-vitro fertilization in a kidney transplant patient was not too long ago, in 1995.5,6 Pregnancy in a kidney transplant recipient continues to remain challenging due to the risk of adverse maternal and fetal complications, side effects of immunosuppression, and a risk of deterioration of allograft function.2 Data on pregnancy outcomes with assisted reproductive technology in kidney transplant recipients is limited from case reports, case series, and single-center studies, which contributes to a critical knowledge gap.7,8 Higher rates of preeclampsia, lower gestation age, and lower birth weights have been reported with assisted reproductive technology in women with chronic kidney disease but did not specifically examine the kidney transplant population.9 To the best of our knowledge, no study to date has examined the impact of assisted reproductive technology on pregnancy outcomes in women with kidney transplants in the United States.
The goal of this study was to determine the risk of adverse pregnancy outcomes with the use of assistive reproductive technology (ART) in the kidney transplant population. Using data from the Transplant Pregnancy Registry International (TPRI), we examined differences in outcomes by conception type between ART pregnancies and natural conception pregnancies among women with kidney transplants.
Methods
Data Source
This retrospective cohort study used data from the Transplant Pregnancy Registry International, which has recruited participants since 1991. To our knowledge, the TPRI is the longest-running voluntary registry of pregnancies after transplant, enrolling participants from 325 diverse academic and community centers and hospitals, from the United States and Canada.10 For the Transplant Pregnancy Registry International, trained research coordinators and physicians follow up with participants within one month after delivery and every 1 to 2 years. Pregnancy information is obtained through patient interviews, questionnaires, and medical record reviews. A question regarding fertility assistance was added to the initial survey at the time of enrollment in 2014. Fertility assistance data were obtained retrospectively during follow-up interviews for prior registry participants.
Eligible participants were recipients of a kidney transplant between March 1968 and July 2022 who were aged 14 years or older at the time of conception with a pregnancy after the kidney transplant. If a participant had more than one post-transplant pregnancy, each pregnancy was treated as a separate encounter. Participants had conception dates between February 1970 and December 2021. Participants were excluded if the conception type was unknown. The Transplant Pregnancy Registry International and its associated studies have been approved by the Advarra institutional review board, and all participants provided oral or written informed consent. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Exposure and Outcomes
The conception type was categorized as ART or natural conception. Assisted reproductive technology included the use of in-vitro fertilization, intrauterine insemination, and medications to stimulate ovulation. We examined the following outcomes a) maternal outcomes: preeclampsia, hypertension during pregnancy, gestational diabetes, and cesarean section; b) fetal/neonatal outcomes: live births, low birth weights, stillbirths, miscarriage, elective termination, ectopic pregnancies, mean gestational age, mean birthweight, neonatal deaths, and birth defects; and the c) graft outcomes: acute rejection and 2-year graft loss.
Pertinent information on demographics and outcomes was abstracted. Race and ethnicity are self-reported. Serum creatinine levels were reported in milligrams per deciliter and were the highest reported values before pregnancy, during pregnancy, and after pregnancy. Birth weight, gestational age, and neonatal death were only considered for fetuses with confirmed live births. Preterm birth was defined as delivery < 37 weeks. Low birth weight was defined as delivery fetal weights < 2500 grams. Miscarriages were defined as pregnancies lost at < 20 weeks of gestation. Acute rejection was defined as biopsy-confirmed histologic rejection during pregnancy. Graft loss was defined as the need for maintenance dialysis or repeat transplant. Hypertension during pregnancy was defined as drug-treated hypertension during pregnancy. Gestational diabetes was defined as insulin-treated diabetes mellitus during pregnancy.
Statistical Analysis
Patient characteristics were described using median and interquartile range (IQR) for continuous variables and count and percent for categorical variables. Differences between groups were tested using chi-squared tests for categorical variables and the Mann-Whitney U tests for continuous variables. For categorical variables with small cell counts, Chi-square tests were replaced with Monte Carlo simulations. To preserve as many values as possible, missing values for discrete variables were included as unique levels but not in chi-square testing.
Univariate and multivariate logistic regression was used to evaluate the association ART compared to natural conception with maternal pregnancy outcomes of gestational diabetes, hypertension during pregnancy, preeclampsia, and cesarean section delivery; fetal and neonatal outcomes of live birth, miscarriage, low birth weight, preterm birth, and birth defects, and graft outcome of 2-year graft loss. Due to small counts for some outcomes, the multivariable logistic models were adjusted only for age at conception and race. The single missing value for conception age was discarded rather than retained as a level in the multivariate logistic regression models. A two-tailed p-value of <0.05 was considered statistically significant. All data were analyzed using SAS 9.4 (SAS Institute, Cary, NC) and R.
Results
The study cohort consisted of 77 participants with 130 ART pregnancies and 695 participants with 1272 natural conception pregnancies after the kidney transplant.
Demographic and Baseline Characteristics
Maternal characteristics by conception type are summarized in Table 1. Women who conceived with both ART and natural conception were mostly White (76.0% vs. 74.6%, p-value = 0.27). The median age at conception was higher with ART pregnancies, 35.0 years (IQR 30.0, 37.8 years), compared to those with natural conception pregnancies, 30.7 years (IQR 27.0, 33.9 years) (p-value < 0.001). In ART pregnancies, the highest proportion had conception ages > 35 years (50%), whereas in natural conception pregnancies, the highest proportion had conception ages of 30–35 years (44.9%). ART pregnancies had a longer median transplant-conception interval than natural conception pregnancies (5.8 years [IQR 3.7, 9.7 years] vs. 4.8 years [IQR 2.5, 8.1 years], p-value < 0.001). ART pregnancies had a higher proportion of twins (9.2% vs. 2.2%), triplets (1.5% vs. 0%), and quadruplets (0.8% vs. 0%), as compared to natural conception pregnancies. Figure 1 shows that the number of ART pregnancies have increased over time in kidney transplant recipients.
Table 1.
Baseline characteristics of natural conception pregnancies and assisted reproductive technology pregnancies in female kidney transplant recipients
| Natural Conception | Assisted Reproductive Technology | ||||
|---|---|---|---|---|---|
|
| |||||
| Unique Individuals (N) | 695 | 77 | p-value | ||
|
| |||||
| N | % | N | % | ||
|
| |||||
| Race | 0.268 | ||||
| White | 497 | 74.6 | 57 | 76.0 | |
| Black | 65 | 9.8 | 4 | 5.3 | |
| Asian | 33 | 5.0 | 7 | 9.3 | |
| Other | 71 | 10.7 | 7 | 9.3 | |
| Missing (n = 31) | |||||
|
| |||||
| Hispanic ethnicity | 0.212 | ||||
| Yes | 57 | 11.8 | 4 | 6.5 | |
| Missing (n = 225) | |||||
|
| |||||
| Total number of transplants | 0.465 | ||||
| 1 | 600 | 86.5 | 66 | 85.7 | |
| 2 | 83 | 12.0 | 11 | 14.3 | |
| > 2 | 11 | 1.6 | 0 | 0.0 | |
| Missing (n = 1) | |||||
|
| |||||
| Pregnancies (N) | 1272 | 130 | |||
|
| |||||
| N | % | N | % | ||
|
| |||||
| Median conception age, year* | 30.7 (27.0 – 33.9) | 35.0 (30.0 – 37.8) | < 0.001 | ||
|
| |||||
| Conception age, years | < 0.001 | ||||
| < 25 | 191 | 15.0 | 4 | 3.1 | |
| 25 – 29 | 275 | 21.6 | 26 | 20.0 | |
| 30 – 35 | 571 | 44.9 | 35 | 26.9 | |
| > 35 | 234 | 18.4 | 65 | 50.0 | |
| Missing (n = 1) | |||||
|
| |||||
| Median transplant to conception interval, years* | 4.8 (2.5 – 8.1) | 5.8 (3.7 – 9.7) | < 0.001 | ||
|
| |||||
| Pre-conception creatinine, mg/dL* | 1.2 (1.0 – 1.4) | 1.1 (1.0 – 1.3) | 0.22 | ||
|
| |||||
| Transplant to conception interval, years | < 0.001 | ||||
| < 1 | 73 | 5.8 | 0 | 0.0 | |
| 1 to 3 | 330 | 26.0 | 20 | 15.4 | |
| 4 to 10 | 651 | 51.3 | 79 | 60.8 | |
| > 10 | 214 | 16.9 | 31 | 23.8 | |
| Missing (n = 4) | |||||
|
| |||||
| Pregnancy number | 0.275 | ||||
| 1 | 662 | 52.0 | 71 | 54.6 | |
| 2 | 356 | 28.0 | 37 | 28.5 | |
| 3 | 167 | 13.1 | 10 | 7.7 | |
| > 3 | 87 | 6.8 | 12 | 9.2 | |
|
| |||||
| Type of gestation | < 0.001 | ||||
| Singleton | 1244 | 97.8 | 115 | 88.5 | |
| Twins | 28 sets | 2.2 | 12 sets | 9.2 | |
| Triplets | 0 sets | 0.0 | 2 sets | 1.5 | |
| Quadruplets | 0 sets | 0 | 1 set | 0.8 | |
|
| |||||
| Immunosuppression during pregnancy | |||||
|
| |||||
| Tacrolimus | 0.006 | ||||
| Yes | 508 | 40.1 | 68 | 52.7 | |
| Missing (n = 6) | |||||
|
| |||||
| Cyclosporine | 0.942 | ||||
| Yes | 496 | 39.1 | 50 | 38.8 | |
| Missing (n = 4) | |||||
|
| |||||
| Azathioprine | 0.799 | ||||
| Yes | 917 | 72.5 | 90 | 71.4 | |
| Missing (n = 11) | |||||
|
| |||||
| Prednisone | 0.085 | ||||
| Yes | 1087 | 86.0 | 101 | 80.2 | |
| Missing (n = 12) | |||||
|
| |||||
| Mycophenolate | 0.001 | ||||
| Yes | 118 | 9.3 | 2 | 1.5 | |
| Missing (n = 9) | |||||
|
| |||||
| Sirolimus | 0.710 | ||||
| Yes | 18 | 1.4 | 2 | 1.6 | |
| Missing (n = 23) | |||||
|
| |||||
| Belatacept | 1.000 | ||||
| Yes | 7 | 0.6 | 0 | 0.0 | |
| Missing (n = 71) | |||||
Reported in median (interquartile range)
Figure 1.
The number of assisted reproductive technology pregnancies show an increasing incidence over time in kidney transplant recipients.
Maternal Outcomes
ART pregnancies had a higher proportion of hypertension during pregnancy than natural conception pregnancies (60.9% vs. 49.4%, p-value = 0.013). The proportion of preeclampsia (40.2% vs. 30.4%, p-value = 0.052) and gestational diabetes (8.1% vs. 8.7%, p-value = 0.084) did not differ significantly between ART and natural conception pregnancies. ART pregnancies had a higher rate of cesarean section deliveries than did the natural conception group (64.0% vs. 51.2%, p-value = 0.015) (Table 2).
Table 2.
Maternal outcomes of natural conception pregnancies and assisted reproductive technology in kidney transplant recipients
| Natural Conception | Assisted Reproductive Technology | p-value | |||
|---|---|---|---|---|---|
|
| |||||
| Pregnancies (N) | 1272 | 130 | |||
|
| |||||
| N | % | N | % | ||
|
| |||||
| Hypertension during pregnancy | 0.013 | ||||
| Yes | 619 | 49.4 | 78 | 60.9 | |
| Missing (n = 20) | |||||
|
| |||||
| Preeclampsia | 0.052 | ||||
| Yes | 284 | 30.4 | 37 | 40.2 | |
| Missing (n = 60) | |||||
|
| |||||
| Gestational diabetes | 0.084 | ||||
| Yes | 103 | 8.7 | 10 | 8.1 | |
| Missing (n = 93) | |||||
|
| |||||
| Cesarean section delivery | 0.015 | ||||
| Yes | 498 | 51.2 | 64 | 64.0 | |
| Missing (n = 15) | |||||
In the multivariate models adjusted for age at conception and race, ART pregnancies were associated with higher odds of hypertension during pregnancy (OR, 1.57; CI, 1.06–2.32) compared to natural conception pregnancies. ART pregnancies were associated with a higher adjusted risk of cesarean delivery (OR, 1.60; CI, 1.02–2.51) compared to natural conception pregnancies. There was no significant difference in the adjusted likelihood of preeclampsia (OR, 1.55; CI, 0.98–2.45) and gestational diabetes (OR, 0.74; CI, 0.37–1.51) in ART vs. natural conception pregnancies (Figure 2).
Figure 2.
The results from the multivariable logistic regression models show unadjusted and adjusted odds ratio in assisted reproductive technology pregnancies compared to natural conception pregnancies predicting the maternal outcomes of preeclampsia, hypertension during pregnancy, gestational diabetes, cesarean section delivery, and 2-year graft loss in kidney transplant recipients.
*Odds ratios are adjusted for covariates of maternal age at conception and race.
Fetal and Neonatal Outcomes
Table 3 shows the pregnancy outcomes with ART and natural conception. ART pregnancies had a higher proportion of preterm births (62.6% vs. 50.0%, p-value = 0.010). The median gestational age was lower in the ART pregnancies as compared to the natural conception pregnancies (36.0 weeks [IQR 32.0, 37.6 weeks] vs. 37.0 weeks [IQR 34.9, 38.0 weeks], p-value < 0.001). The ART group had a lower median birth weight than the natural conception group (2551.0 grams [IQR 1587.6, 2891.7 grams] vs. 2722.0 grams [IQR 2211.3, 3118.0 grams], p-value < 0.001). There was a higher proportion of neonatal deaths in ART pregnancies than in natural conception pregnancies (4.4% vs. 0.8%, p-value = 0.007). The proportion of live births did not differ significantly between ART and natural conception pregnancies (77.2 % vs. 76.5%). The proportion of miscarriage, termination, stillbirth, and ectopic pregnancies did not differ significantly between the two groups. The proportion of low birth weights (47.7% vs. 39.9%, p-value = 0.115) and birth defects (8.7% vs. 6.4%, p-value = 0.324) did not differ significantly between ART and natural conception pregnancies.
Table 3.
Fetal and neonatal outcomes of natural conception pregnancies and assisted reproductive technology pregnancies in kidney transplant recipients
| Natural Conception | Assisted Reproductive Technology | p-value | |||
|---|---|---|---|---|---|
|
| |||||
| N | 1300 | 149 | |||
|
| |||||
| N | % | N | % | ||
|
| |||||
| Birth Outcome | 0.419 | ||||
| Live Birth | 995 | 76.5 | 115 | 77.2 | |
| Miscarriage | 240 | 18.5 | 30 | 20.1 | |
| Termination | 37 | 2.9 | 1 | 0.7 | |
| Stillbirth | 18 | 1.4 | 1 | 0.7 | |
| Ectopic | 10 | 0.8 | 2 | 1.3 | |
|
| |||||
|
*Low birth weight (< 2500 grams) |
0.115 | ||||
| Yes | 395 | 39.9 | 52 | 47.7 | |
| Missing (n = 11) | |||||
|
| |||||
| *Median birth weight, grams+ | 2722.0 (2211.3 – 3118.0) | 2551.0 (1587.6 – 2891.7) | <0.001 | ||
|
| |||||
| *Preterm birth (< 37 weeks) | 0.010 | ||||
| Yes | 496 | 50.0 | 72 | 62.6 | |
| Missing (n = 2) | |||||
|
| |||||
| *Median gestational age, weeks+ | 37.0 (34.9 – 38.0) | 36.0 (32.0 – 37.6) | < 0.001 | ||
|
| |||||
| *Neonatal death | 0.007 | ||||
| Yes | 8 | 0.8 | 5 | 4.4 | |
| Missing (n = 5) | |||||
|
| |||||
| Birth defects | 0.324 | ||||
| Yes | 63 | 6.4 | 10 | 8.7 | |
| Missing (n = 8) | |||||
Designates calculation for live births only
Reported in median (interquartile range)
In the adjusted multivariate models, ART pregnancies compared to natural conception pregnancies were associated with higher odds of preterm births (OR, 2.07; CI, 1.35–3.18). There were no significant differences in the adjusted likelihood of live births (OR, 1.07; CI, 0.69–1.65), miscarriages (OR, 0.92; CI, 0.59–1.45), low birth weights (OR, 1.48; CI, 0.97–2.26), or birth defects (OR, 1.43; CI, 0.68–3.01) in the ART vs. natural conception pregnancies (Figure 3).
Figure 3.
The results from the multivariable logistic regression models show unadjusted and adjusted odds ratio (95% confidence interval) in assisted reproductive technology pregnancies compared to natural conception pregnancies predicting fetal outcomes of live births, preterm births, low birthweights, miscarriages, and birth defects in kidney transplant recipients.
*Odds ratios are adjusted for covariates of maternal age at conception and race.
Graft Outcomes
The median highest creatinine did not differ significantly between the ART and the natural conception pregnancies (pre-pregnancy creatinine - 1.2 mg/dl [IQR 1.0, 1.4 mg/dl] vs. 1.1 mg/dl [IQR, 1.0, 1.3 mg/dl], p = 0.22); creatinine during pregnancy (pre-pregnancy creatinine - 1.2 mg/dl [IQR 1.0, 1.5 mg/dl] vs. 1.2 mg/dl [IQR, 1.0, 1.5 mg/dl], p = 0.97) and postpartum creatinine - 1.2 mg/dl [IQR 1.0, 1.5 mg/dl] vs. 1.2 mg/dl [IQR, 1.0, 1.4 mg/dl], p = 0.57). Acute rejection did not differ significantly between the ART and the natural conception pregnancies (3.2% vs. 2.7%, p = 0.77). The 2-year graft loss did not differ significantly between the ART and the natural conception pregnancies (8.4% vs. 5.6%, p = 0.27) (Table 4).
Table 4.
Kidney graft outcomes of natural conception pregnancies and assisted reproductive technology pregnancies in kidney transplant recipients.
| Natural Conception | Assisted Reproductive Technology | p-value | |||
|---|---|---|---|---|---|
|
| |||||
| Pregnancies (N) | 1272 | 130 | |||
|
| |||||
| Median serum creatinine, mg/dL* | |||||
| Pre-Pregnancy (n = 1177) | 1.2 (1.0 – 1.4) | 1.1 (1.0 – 1.3) | 0.22 | ||
| During Pregnancy (n = 1173) | 1.2 (1.0 – 1.5) | 1.2 (1.0 – 1.5) | 0.97 | ||
| Postpartum (n = 1094) | 1.2 (1.0 – 1.5) | 1.2 (1.0 – 1.4) | 0.57 | ||
|
| |||||
| Acute rejection | 0.77 | ||||
| Yes | 34 | 2.7 | 4 | 3.2 | |
| Missing (n = 27) | |||||
|
| |||||
| 2-year graft loss | 0.27 | ||||
| Yes | 65 | 5.6 | 9 | 8.4 | |
| No | 1107 | 94.5 | 98 | 91.6 | |
| Not applicable < 2 years elapsed | 85 | 23 | |||
| Missing (n= 15) | |||||
|
| |||||
Reported in median (interquartile range)
In the multivariable models, there was no difference in the adjusted likelihood of 2-year graft loss in ART pregnancies as compared to natural conception pregnancies (OR, 1.95; CI, 0.90–4.22).
Discussion
This study employs the largest cohort to date of kidney transplant recipients reporting pregnancy outcomes using ART to date. Our findings demonstrated a higher maternal age, a higher transplant-conception interval, a higher proportion of multi-fetal birth, and a higher proportion of neonatal deaths with ART pregnancies as compared to natural conception pregnancies. We also showed a higher adjusted risk of hypertension during pregnancy, cesarean delivery, and preterm births with ART pregnancies than natural conception pregnancies in kidney transplant recipients.
Our study shows that females receiving assisted fertility treatments were older than their naturally conceiving counterparts, with a median age at conception of 35 years, consistent with data from other single-center studies in Sweden (mean maternal age – 32 years) and Turkey (mean maternal age – 33 years).7,8 This could be due to the years spent trying to conceive unsuccessfully and the effect that maternal age has on ovarian function, even in the general population, where advancing age is associated with falling anti-Mullerian hormone levels and ovulatory capacity, with kidney disease further impacting that natural decline.11,12
We noted a longer time to conception with ART pregnancies with a median transplant-conception interval of 5.8 years. According to the American Society of Transplantation, conception is safe after 1 to 2 years post-transplantation, while European guidelines suggest waiting two years after transplantation. 13,14 Our findings suggest that females who required fertility assistance may have faced challenges in conceiving in the earlier post-transplant period.7 Also, ART takes a lot of time, and women may have tried to conceive naturally and failed before getting ART. There may be financial barriers to access to ART that may have taken additional time to overcome.
The present study found a higher proportion of twins and triplets with ART pregnancies. Bhaduri et al. reported a multiple birth rate was 15.6% in their systemic review of ART pregnancies in kidney transplant recipients.9 Although ART may increase the incidence of multifetal pregnancies, data from the Human Fertilization and Embryology Authority suggest that multi-fetal pregnancies account only for 8% of ART pregnancies.15 Over the past ten years, there has been a growing trend in the UK and USA to opt for single-embryo transfer, resulting in a significant decrease in multi-fetal pregnancies consistent with our study results16.
We identified a higher risk of hypertension during pregnancy but not of preeclampsia with ART pregnancies among kidney transplant recipients. The greater risk of hypertensive disorders in pregnancy with assisted fertility treatments is well-established.17 A meta-analysis of 15 studies in the non-transplant population found a 1.5-fold higher risk of hypertensive disorders during pregnancies with IVF/intracytoplasmic sperm injection than natural conception.18 However, the use of ART did not increase the risk of preeclampsia in the present study. Pregnancies achieved through frozen embryo transfer without the corpus luteum in the general population are associated with a higher risk of preeclampsia.8 The incidence of preeclampsia is also higher in kidney transplant recipients than in the general population and reflects the impact of longstanding CKD, history of hypertension, and potential immunosuppression effects, especially calcineurin inhibitors.2,19 Warzecha et al. reported a case series of 3 kidney transplant patients who developed severe preeclampsia following IVF.20 Contrary to this, another study showed a higher percentage of preeclampsia in kidney transplant recipients who underwent spontaneous conception (23.6%) compared to the IVF group (14.3%).8 Hypertension is common in kidney transplant recipients, with incidence ranging from 52%–69%.4 Several factors may contribute to the onset of hypertension after kidney transplantation, including the type of immunosuppressive therapy (calcineurin inhibitors and corticosteroids) and allograft function. The higher incidence of pre-existing hypertension and proteinuria in kidney transplant recipients makes the diagnosis of superimposed preeclampsia challenging in women with chronic hypertension and /or preexisting proteinuria.2,4 Also, substantial changes in diagnostic criteria for preeclampsia over the study period, as underscored by the International Committee of the International Society for the Study of Hypertension in Pregnancy (ISSHP), may have led to incorrect classification for preeclampsia.21 Further studies with larger sample sizes are needed to explore the association between preeclampsia and ART in kidney transplant recipients.
ART pregnancies, as compared to natural conception pregnancies, were associated with a higher likelihood of cesarean deliveries in kidney transplant recipients, consistent with the prior literature. 8,20,22 In a retrospective study, Norrman et al. found that cesarean section rates were 85.7% in the IVF group and 61.3% in the spontaneous conception group among kidney transplant recipients.8 A systemic review of women with CKD found a similar association with higher rates of cesarean deliveries with ART than with spontaneous conception (89.5% vs. 62.6%).9 The higher risk of cesarean deliveries with ART may be attributed to patient preference, clinician hesitancy to allow trial of labor, preterm birth and higher risk of breech position, and maternal medical complications that may require emergency delivery particularly pre-eclampsia.23 While the reasons are not clear, factors like older maternal age , preterm birth, low birth weight and increased placental index, which are more common in ART pregnancies, might contribute to breech presentation. 24 Cesarean delivery may be perceived as a more “controlled” form of delivery. There may also be an assumption that transplanted women should not be delivered vaginally. However, unless there is an obstetric indication for cesarean delivery, vaginal delivery is recommended for kidney transplant recipients.25
There were higher odds of preterm births and lower mean gestation age with ART pregnancies versus natural conception pregnancies, consistent with data in the general obstetric population.18 Women with CKD and ART have a seven-fold higher rate of preterm delivery compared to the general population in the United States (35.3% vs. 3.8%). 9 Preterm birth rates of 40–60% are observed in kidney transplanted mothers.10 Assisted fertility treatments may augment that risk due to multiple factors, including maternal age, abnormal placental development, and multiple pregnancies.13 Our study also found similar live birth rates in the natural conception and the ART groups with no significant differences in other key adverse outcomes of miscarriage, termination, and stillbirth, consistent with prior literature.9 Although the incidence of low-birth-weight neonates was similar in the two groups, the mean birth weight was lower in the fertility-assisted group, likely due to the higher rate of multifetal pregnancies. There is a documented increased risk of preterm delivery and intrauterine growth restriction among kidney transplant recipients. Adding to this, the perinatal risk of low birth weight, prematurity, and small for gestational age in ART patients suggests that we might expect kidney transplant patients utilizing ART to be at especially high risk of delivering babies with lower birth weights and lower gestation age. These findings are crucial for providers to understand and convey to kidney transplant recipients who are considering fertility assistance.
With regards to kidney allograft outcomes, our study found no differences in acute rejection and 2-year graft loss between the ART and natural conception groups. In a single-center experience on IVF after kidney transplantation, among 13 transplant patients, one patient had a graft rejection after IVF, while serum creatinine levels increased more than 30% in three patients after the IVF procedure; nine patients had minimal or no change in serum creatinine levels.7 A literature review by Pietrzak et al. on successful pregnancies after in vitro fertilization in solid organ recipients from 1995 to 2014 reported only a single case of kidney graft function deterioration due to renal obstruction by enlarged ovaries due to ovarian hyperstimulation syndrome.22 Findings from our large-sampled study suggest that despite the higher risk of maternal and fetal complications associated with ART in kidney transplant recipients, there is no impact on the functioning of transplanted kidneys short term.
The study’s strength lies in its use of well-established data from TPRI, encompassing a large sample size from the United States and Canada, spanning several decades (1967–2022), which represents one of the largest cohort studies on pregnancy outcomes with assisted fertility to date in kidney transplant recipients. We therefore provide much-needed data to inform pre-pregnancy counseling regarding ART in the kidney transplant population. The limitations of the study include the use of a voluntary registry and reporting bias and recall bias.
In conclusion, in kidney transplant recipients using ART, the study demonstrates an increase in the risk of hypertension during pregnancy, preterm births, and cesarean delivery. However, despite these risks, there were no significant differences in the likelihood of live birth rate and in 2-year graft survival between women who received assisted fertility and those who conceived naturally. This finding can be valuable for healthcare providers as it helps them offer preconception counseling and informed guidance when assisting individuals who wish to start a family after a kidney transplant. The study contributes essential data to the limited literature on pregnancy outcomes in kidney transplant recipients utilizing fertility assistance.
Funding
Silvi Shah is supported by the National Institutes of Health (NIH) K23 career development award, under Award Number 1K23HL151816-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders of the study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.
Footnotes
Competing interests
All the authors have no disclosures and competing interests for the submitted work. The results presented in this paper have not been published previously in whole or part, except in abstract format.
Data Sharing Statement
Data that support the findings are included within the manuscript.
References
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Data Availability Statement
Data that support the findings are included within the manuscript.