Pregnancy, Where Assisted Reproductive Technology and Transplant Science Intersect

In this issue of Transplantation, Shah et al1 draw on US and Canadian data from the Transplant Pregnancy Registry International to characterize the maternal, fetal, and allograft outcomes associated with assisted reproductive technology (ART). The result is the most comprehensive assessment to date of ART outcomes in women with kidney transplants. Kidney transplantation restores the hypothalamic-pituitary-gonadal axis, greatly improving ovarian function in women of reproductive age suffering from chronic kidney disease. Most women with kidney transplants conceive naturally; however, infertility remains a challenge for some due to incomplete restoration of ovarian function, higher transplant-to-conception time interval, older maternal age, or underlying medical issues. ART is a generic term that encompasses several procedures including in vitro fertilization (IVF) and non-IVF procedures including ovulation induction, artificial insemination, and intrauterine insemination. Since the 1978 birth of Louise Brown, the first ART baby, >12 million IVF live births have been reported. The number of IVF cycles in the United States has nearly doubled from 2000 through 2013 accounting for 1.7%–2% of all live births.2 In 1995, Lockwood et al3 reported the first IVF birth in a transplant recipient. Since that time, data guiding ART use in kidney transplant recipients have been limited to case reports, case series, and single-center studies. This retrospective study, using Transplant Pregnancy Registry International data encompassing 77 participants with 130 ART pregnancies and 695 participants with 1272 natural conceptions, compares maternal, fetal/neonatal, and graft outcomes between ART and natural conception, between the years of 1968 and 2022.1 The authors demonstrated a higher likelihood of hypertension, premature deliveries, cesarian sections (C-sections), lower birth weights (LBWs), and neonatal deaths with ART. The absolute number of neonatal deaths was small, perhaps explained by the higher prevalence of multifetal gestations in the ART group. The study results align with the maternal and neonatal outcomes in the general population, where ART carries an increased risk of hypertensive disorders of pregnancy, placental complications, preterm delivery, and C-sections as well as an increased risk of LBW babies.2,4 In contrast, transplant recipients are known to be at a higher risk of adverse pregnancy outcomes with a reported incidence of preeclampsia of 24%–38% compared with 3%–4% among the general population and a reported C-section incidence of ~60% compared with 31.9% in the general US population.5,6 Additionally, transplant recipients have a 12-fold higher risk of delivering LBW babies and a 13-fold greater risk of preterm deliveries.7 This study highlights several notable areas that warrant further exploration. Notably, 9.2% of transplant recipient pregnancies were conceived via ART, a rate significantly higher than the 2.6% observed in the general US population, despite reportedly similar rates of infertility.8 Interestingly, preeclampsia rates in the ART cohort were not elevated compared with the natural conception group, possibly reflecting a high baseline risk of preeclampsia among transplant recipients that diminishes the relative contribution of ART. It is also conceivable that certain ART protocols may confer protective effects. The specific type of ART (eg, IVF versus ovulation induction) and factors such as fresh versus frozen embryo transfer may differentially influence outcomes. Frozen embryo transfers are associated with a higher risk of preeclampsia due to a higher likelihood of suboptimal placentation and maternal cardiovascular adaptation.9 Advances in preeclampsia biomarkers may improve diagnostic accuracy in pregnant transplant recipients. The higher rate of cesarean delivery in ART pregnancies may reflect either true obstetric indications or a more cautious approach by clinicians. Additionally, the impact of ART pregnancies on postpregnancy glomerular filtration rate decline remains unclear. The role of ovarian hyperstimulation syndrome—a complication unique to ART—warrants special attention in transplant recipients, as their response may differ from nontransplant patients. Finally, it is important to assess whether these findings apply to recipients of grafts with preexisting dysfunction or scarring and whether they are generalizable to transplant populations outside North America. Independent of unanswered questions, this study offers critical insights for providers and transplant patients considering pregnancy. Notably, ART pregnancies were more common in older women (median age 35 versus 30.7) and those with longer transplant-to-conception intervals. These women may represent those who tried and failed at natural conception, resulting in delayed childbearing. Providers should understand the potential for reproductive delays and proactively discuss fertility preservation and ART options early after transplant, if not before. The increased incidence of multifetal gestations highlights the importance of single-embryo transfer and early collaboration with reproductive endocrinologists to mitigate risks. Early involvement of maternal-fetal medicine specialists familiar with transplant physiology is also important, given the higher rates of hypertensive disorders. The study provides important and novel insights into risks of ART in kidney transplant recipients and will be a resource for counseling infertile transplant patients. As newer ART protocols and immunosuppressive regimens evolve, ongoing registry data will be essential to reassess these risks. Moreover, the inclusion of patient-reported outcomes, including satisfaction with reproductive care and quality of life, would further enrich the data and enhance its usefulness. Importantly, this study provides evidence-based reassurance for patients and clinicians that while ART increases certain obstetric risks, it does not adversely affect graft outcomes or overall likelihood of live birth. These data support a balanced, informed approach to fertility planning in this population. We commend the authors for their investigation of an understudied area in posttransplant women’s health that has been subject to speculation and controversy. For providers and patients navigating the complex intersection of transplantation and fertility, this report from the largest available transplant registry of patients from North America provides confidence that ART is a viable and increasingly accessible option for women with kidney transplants, provided it is pursued with careful planning, appropriate surveillance, and interdisciplinary collaboration.

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