Living Donation and Pregnancy-Related Complications

Abstract

Living kidney donation and living liver donation significantly increases organ supply to make lifesaving transplants possible, offering survival benefits to the recipients and cost savings to society. Of all living donors, 40% are women of childbearing age. However, limited data exist regarding the effect of donation on future pregnancies and of pregnancy-related complications on postdonation outcomes. In February 2023, the American Society of Transplantation Women's Health Community of Practice held a virtual Controversies Conference on reproductive health, contraception, and pregnancy after transplantation and living donation. Experts in the field presented the available data. Smaller breakout sessions were created to discuss findings, identify knowledge gaps, and develop recommendations. We present the conference findings related to living donation. The evidence reviewed shows that gestational hypertension and gestational diabetes mellitus before kidney donation have been associated with an increased risk of developing postdonation hypertension and diabetes mellitus, respectively, without increasing the risk of developing an eGFR <45 ml/min after donation. The risk of preeclampsia in living kidney donors increases to 4%–10%, and low-dose aspirin may help reduce that risk. Little is known about the financial burden for living donors who become pregnant, their risk of postpartum depression, or the optimal time between donation and conception. The data on living liver donors are even scarcer. The creation of a registry of donor candidates may help answer many of these questions and, in turn, educate prospective donors so that they can make an informed choice.

Introduction

The optimal and often lifesaving treatment of patients with ESKD and end stage liver disease is transplantation. Because of the scarcity of organs, more than 100,000 individuals are awaiting organ transplantation in the United States alone.¹ Living kidney donors (LKDs) and living liver donors (LLDs) play a key role by significantly enlarging the donor pool, reducing wait times, and providing a survival advantage to the recipient. Women of childbearing potential represent approximately 40% of all living donors (LDs).¹ Therefore, a significant proportion of LDs have the potential for predonation and postdonation health to be affected by pregnancy. Consequently, it becomes imperative to understand and communicate the risk of pregnancy-related complications during LD evaluations.

To address pressing topics related to reproductive health of LDs and transplant recipients, the American Society of Transplantation (AST) Women’s Health Community of Practice (WHCOP) held a virtual Controversies Conference in February 2023. Experts met for 2 days to discuss the topics of parenthood and reproductive health in LDs and transplant recipients. The conference methodology is summarized in Table 1. We summarize the evidence and discussion regarding the risk of living donation on future pregnancies and the implications of pregnancy-related complications in LD risk assessment and selection. Finally, we identify current knowledge gaps and areas for future research. This article is a work product of the AST WHCOP.

Table 1.

Reproductive health, contraception, and pregnancy after transplantation and living donation Controversies Conference: methodology

Organizer

AST WHCOP

Dates

February 14 and 15, 2023

Objectives

1. Determine the safety and timing for a SOT recipient to conceive

2. Develop recommendations for SOT recipients seeking contraception or assisted fertility considering the changing legal landscape after the Supreme Court overturned Roe v. Wade

3. Provide recommendations for pregnancy and contraception surrounding living donation

Participant selection

Experts in the field were identified through review of the literature, authors of prior consensus guidelines, and leaders in women's health from professional societies

Process

1. Experts presented the available data and divided in smaller breakout sessions to discuss findings, identify knowledge gaps, and develop recommendations

2. Three workgroups were created to address each specific objective

3. The living donation workgroup consisted of nine experts who reviewed and discussed the current literature and state of practice regarding how pregnancy-related complications can affect future LD outcomes and how living donation can increase the risk of pregnancy-related complications

Workgroups

Participants were divided in the following three workgroups according to their expertise

1. Pregnancy and contraception after solid organ transplantation

2. Assisted reproductive technologies and reproductive health for SOT recipients

3. Pregnancy and contraception surrounding living donation

Participants, Institutions, and Represented Fields
Name	Institution	Specialty/Expertise	Workgroup
Yalda Afshar, MD, PhD	University of California Los Angeles	Obstetrics and Gynecology	1
Julie Bonn, MD	Cincinnati Children's Hospital Medical Center	Pediatrics/hepatology/transplant recipient	1
Carla Brady, MD, MHS	Duke University Medical Center	Hepatology	3
Jennifer Byrns, CPP, PharmD	Duke University Hospital	Pharmacy	1, 2
Jillian P. Casale, PharmD	University of Maryland Medical Center	Pharmacy	1
Serban Constantinescu, MD	Temple University	Nephrology/TPRI	1
Lisa Coscia, RN, BSN	TPRI	Registered Nurse/Research Coordinator	1, 2, 3
Ersilia DeFilippis, MD	Columbia University Irving Medical Center	Cardiology	1, 2
Christina Doligalski, PharmD	University of North Carolina	Pharmacy	3
Lauren Feld, MD	UMASS Chan Medical School	Hepatology	1, 2
Roshan George, MD	Emory University	Pediatrics Nephrology	1
Aviva Goldberg, MD	University of Manitoba	Ethics/Pediatrics Nephrology	1, 2
Ana Iltis, PhD	Wake Forest University	Ethics	1
Roxanna Irani, MD PhD	University of California San Francisco	Maternal–Fetal Medicine	3
Shilpa Jesudason, MBBS, PhD	University of Adelaide	Nephrology	1
Goni Katz-Greenberg, MD, MS	Duke University Medical Center	Nephrology	1, 2, 3
Michelle M. Kittleson, MD, PhD	Cedars-Sinai	Cardiology	1
Krista Lentine, MD PhD	Saint Louis University School of Medicine	Nephrology	3
Deborah Levine, MD	Stanford University	Pulmonology	1, 3
Fred Licciardi, MD	New York University Langone	Reproductive Endocrinology	1, 2
Arthur Matas, MD	University of Minnesota	Surgery	3
Michael Moritz, MD	Gift of Life Donor Program TPRI	Surgery	1
Kathleen E. O'Neill, MD	Perelman School of Medicine at the University of Pennsylvania	Obstetrics and Gynecology	1, 2
Swati Rao, MD	University of Virginia	Nephrology	1, 2
Ana Rossi, MD, MPH	Piedmont Transplant Institute	Nephrology	1, 2, 3
Monika Sarkar, MD MSc	University of California, San Francisco	Hepatology	1
Silvi Shah, MD, MS	University of Cincinnati	Nephrology	1, 3
Alexandra Shingina, MD, MSc	Vanderbilt University Medical Center	Hepatology	1, 2
Kim Uccellini	United Network of Organ Sharing	Transplant Recipient	1

AST, American Society of Transplantation; LD, living donor; SOT, solid organ transplant; TPRI, Transplant Pregnancy Registry International; WHCOP, Women's Health Community of Practice.

Donor Evaluation, Outcomes, and Selection

Does a History of Predonation Gestational Diabetes, Gestational Hypertension, or Preeclampsia Increase the Risk of Complications after Donation?

Preeclampsia is a pregnancy-specific hypertensive disorder with multisystem involvement that has significant long-term effects. In the general population, hypertension (HTN) in pregnancy, including preeclampsia and gestational HTN (GHTN), is an independent risk factor of chronic HTN, cardiovascular disease (CVD), and stroke.^2–4 Preeclampsia also increases the future risk of CKD, which is compounded with each preeclamptic pregnancy.⁵ A study of 1862 LKDs with predonation pregnancies were followed by a median time of 18 years after donation (interquartile range, 9.2–27.7) and donated at a median time of 18.5 years after the first pregnancy (interquartile range, 10.6–27.5).⁶ GHTN before donation was associated with an increased risk of developing postdonation HTN (hazard ratio [HR], 1.89; 95% confidence interval [CI], 1.26 to 2.83). In contrast to the general population, LKDs with predonation preeclampsia/eclampsia did not have a higher risk of developing HTN or CKD in this study, but there was a trend toward increased risk of CVD (HR, 1.91; 95% CI, 0.94 to 3.88). Predonation gestational diabetes mellitus (GDM) was associated with increased risk of diabetes mellitus (DM) after donation (HR, 3.04; CI, 1.33 to 6.99). These risks are not higher than in the general population, and none of these predonation conditions were associated with reduced kidney function after donation (defined as an eGFR <45 ml/min per 1.73 m² measured at least 6 months after donation and calculated using the 2009 CKD Epidemiology Collaboration equation).⁷ When interpreting these data, it is vital to remember that 94% of LKDs were White, 88% were non-Hispanic, and average body mass index (BMI) at donation was 25.7 kg/m². It is conceivable that non-White donors, Hispanic donors, and donors with a higher BMI may have higher risks after donation. Studies from the general population have shown that the risk of developing postpregnancy HTN and DM in women with these conditions during pregnancy is greater early after pregnancy and the relative risk decreases with time.^8–10 Therefore, women who donate several years after their pregnancy and have not yet developed these conditions (many of which would exclude them as LKD) may be at lower risk than average (Table 2).

Table 2.

Key findings

• GHTN and GDM before kidney donation have been associated with an increased risk of developing postdonation HTN and diabetes, respectively

• GHTN, GDM, and preeclampsia before kidney donation have not been associated with eGFR <45 ml/min after donation

• There is a small but real increased risk in preeclampsia after kidney donation (4%–10%)

• Preeclampsia in the general population is associated with an increased risk of HTN, ischemic CVD, CKD, and postpartum depression

• Randomized controlled trials in the general population have demonstrated a moderate reduction in preeclampsia rates with the use of aspirin

• A 6-mo waiting period between donation and conception should be considered to allow the kidney function to stabilize

• Most studies with LDs were performed in non-Hispanic White individuals limiting the generalization of findings

• The creation of a registry of donor candidates and long-term follow-up of donors is essential to further understand their risks and outcomes

CVD, cardiovascular disease; GDM, gestational diabetes mellitus; GHTN, gestational hypertension; HTN, hypertension; LD, living donor.

A few guidelines address these risks. The 2017 Kidney Disease Improving Global Outcomes (KDIGO) states that a woman with a prior hypertensive disorder of pregnancy may be acceptable for donation if her long-term postdonation risks are acceptable¹¹; however, determining acceptable risk remains a topic of debate. The 2014 Canadian Kidney Paired Donation Protocol states that premenopausal potential donors with a history of preeclampsia within 10 years or preeclampsia in recurrent pregnancies or history of preeclampsia and planning future pregnancies should be excluded from donation.¹² Regarding history of GDM, the 2017 KDIGO guideline recommends candidates with such a history undergo a two-hour glucose tolerance test or hemoglobin A1c for further characterization. The decision to approve a donor candidate with prediabetes or type 2 DM should be individualized on the basis of demographic and health profiles in relation to the transplant program's acceptable risk threshold. In parallel to the recommendations of the 2017 KDIGO guideline, the Organ Procurement and Transplantation Network (OPTN) LD Policy was updated in 2022 to remove type 2 DM as an exclusion to donation and qualify as diabetes-related exclusion as type 1 or type 2, where an individualized assessment of donor demographics or comorbidities reveals either evidence of end organ damage or unacceptable lifetime risk of complications.¹³ Tools such the CKD Prognosis Consortium Risk tool (http://transplantmodels.com/esrdrisk/) provide a framework for integrated assessment of lifetime risks on the basis of a candidate's profile of demographic and health characteristics, but more work is needed to quantify and incorporate the effect of GDM on lifetime risks. By contrast, the guidelines for Caring for Australasians with Renal Impairment list GDM as an absolute contraindication to LKD.¹⁴

Further research is needed to understand the risk of predonation pregnancy-related complications on postdonation outcomes; the influence of race and ethnicity, BMI, eGFR at donation, and genetic factors on those outcomes have yet to be determined. Although the absolute risk of pregnancy-related complications in postdonation outcomes remains low, a multidisciplinary team effort is needed to identify and individualize risk in potential women LDs of childbearing age. As for the general population with these conditions, women LD candidates with a history of preeclampsia, GHTN, and GDM should be counseled about the potential higher risk of preeclampsia in subsequent pregnancies, higher risk of HTN and DM later in life, and potential higher long-term risk of CVD and CKD. They should also be made aware that it is unknown whether donation changes their long-term risk of these conditions.

What are the Postdonation Pregnancy-Related Complications?

Preeclampsia is estimated to affect 4.6% of pregnancies worldwide,¹⁵ with an estimated prevalence in the United States of 3.4%.¹⁶ Risk factors for the development of preeclampsia include chronic HTN, DM, obesity, and antiphospholipid syndrome, with prior preeclampsia as the most significant known risk factor (relative risk, 8.4).¹⁷

A systematic review of pregnancy after living kidney donation showed an increased risk of preeclampsia of 1%–3% before donation and 4%–10% after donation.¹⁸ The risk of adverse fetal and neonatal outcomes was no different before and after donation. A study of 106 pregnancies after donationfound a higher risk of preeclampsia (2.6% before donation versus 5.7% after donation).¹⁹ The mean time from donation to delivery was 5 years. Ibrahim et al. found that LKDs who became pregnant 2.5–5.1 years after donation had a higher risk of GHTN (0.5% versus 3.5%), preeclampsia (0.5% versus 3.5%), and proteinuria (1.5% versus 4.6%). The risk was greater for women with a history of preeclampsia, GDM, and GHTN (odds ratio, 8.21).²⁰ Interestingly, LKDs with a median age ≤30 years at delivery had a greater risk of preeclampsia/eclampsia than nondonors (odds ratio, 4.09; CI, 1.07 to 15.59).²¹ The mean time from donation to delivery was 2.7 years. A main limitation of studies comparing outcomes before and after donation is that by nature, all donors are older after donation and, similar to the general population, they would be at higher risk of preeclampsia. In addition, it is possible that LKD candidates with a history of preeclampsia were excluded from donation, contributing to lower predonation preeclampsia rates than in the general population. Finally, these studies tend to be of a small sample size^19,21 and retrospective in nature, with outcome ascertainment through chart review or donor questionnaire,²⁰ limiting the quality of the data.

How Long Should a LD Wait between Donation and Conception?

The abovementioned data do not reveal whether the timing of conception after living donation affects pregnancy-related outcomes and whether there were self-determined or provider-derived concerns about pregnancy risks that may have influenced the timing of conception. On the basis of very limited, uncontrolled data, a 2005 report of the Amsterdam Forum on the care of the LKD recommends to delay pregnancy at least 2 months.²² Subsequently, expert opinion has suggested to delay pregnancy at least 1 year after donation.²³ The rationale for a waiting period after donation is to allow kidney function to compensate and stabilize before subjecting the kidney to a new hyperfiltrating state. However, prospective data are needed to determine the optimal duration of time to wait before conceiving a pregnancy and whether there are factors influencing pregnancy-related outcomes after donation. In addition to medical risks, the age of the mother and psychosocial needs should be considered. Additional data are required to understand the effect of living donation on fertility and the perceptions of risks of pregnancy in LD. Until more information becomes available, we believe it is prudent to delay conception for at least 6 months after donation, consistent with other guidance.^22,23

What are the Implications of Preeclampsia on Long-Term Outcomes for Kidney Donors and Nondonors?

Given the associations of LKD with increased risk of preeclampsia, it is important to understand the lasting consequences of this diagnosis so that donor candidates can be informed during evaluation. Preeclampsia can affect obstetric, maternal, and psychosocial outcomes.

From an obstetric perspective, in nondonors, it has been clearly documented that prior preeclampsia increases the likelihood of preeclampsia with subsequent pregnancies. Incidence further increases to nearly 30% when multiple previous pregnancies have been complicated by preeclampsia.²⁴

Beyond the immediate maternal morbidity and mortality associated with preeclampsia, long-term complications are increasingly evident. The most well-documented chronic complications of preeclampsia include early-onset HTN, ischemic CVD, and cardiovascular death.²⁵ While HTN is a known contributor to CKD, the effect of preeclampsia specifically on the development of CKD after pregnancy is less clearly defined. A 2020 systematic review of 23 articles identified that, when adjusted for comorbidities, preeclampsia was associated with a relative risk of CKD of 2.27 (2.02–2.55) and a relative risk of ESKD of 4.90 (3.56–6.74).²⁶ This risk increased dramatically when preeclampsia was superimposed on prepartum HTN, with adjusted relative risk of ESKD estimated at 44.72 (22.59–88.52). Inversely, reports demonstrate that preexisting renal dysfunction, independent of CKD staging, increased the risk of preeclampsia more than two-fold.²⁷

The data regarding long-term outcomes in LKDs are much scanter. A recent single-center cohort study looked into the long-term effects of postdonation pregnancy-related complications for LKD.²⁸ In this mainly White population (92%) composed of 384 donors with postdonation pregnancies, preeclampsia (HR, 2.7; 95% CI, 1.53 to 4.77) and GHTN (HR, 2.39; 95% CI, 1.24 to 4.60) were associated with HTN later in life. Both preeclampsia (HR, 2.15; 95% CI, 1.11 to 4.16) and GDM (HR, 5.60; 95% CI, 1.41 to 22.15) were associated with the development of DM later on. None of these pregnancy-related complications were associated with higher risk of CVD or eGFR <45 ml/min per 1.73 m² measured at least 6 months after donation (calculated using the 2009 CKD Epidemiology Collaboration equation).⁷

When considering resource utilization, preeclampsia in nondonors increases the risk of kidney-related hospitalizations 2.65-fold²⁶ and the utilization of health care access, primarily with general practitioners as compared with visits with a specialized outpatient clinic, such as cardiology²⁹ or nephrology.³⁰ This highlights the potential opportunity for establishment of early specialized care in a population at high risk of long-term morbidity and mortality.^25,31 A meta-analysis found that women with preeclampsia have an increased risk of postpartum depression and more severe depressive symptoms.³² To date, there are no donor-specific data related to resource utilization during pregnancy and postpartum depression.

OPTN Policy 14 requires that women LKD candidates be informed of the increased risk of GHTN and preeclampsia after donation. Given the long-term complications associated with preeclampsia, LKD candidates should also be informed of these potential implications so that they can decide on the timing of donation because they may want to consider completing their family before donating. Although this is difficult to predict.

Can Aspirin Intake Help Prevent Preeclampsia after Living Donation?

In nondonors, a number of randomized control trials and meta-analyses demonstrate a moderate reduction in the rate of preeclampsia with the use of aspirin in pregnancy, without maternal or fetal harm, including congenital anomaly or increased rate of maternal hemorrhage.^33–36 On the basis of these findings, it is recommended that LKDs start aspirin 81 mg nightly from 12 weeks of pregnancy until delivery. Depending on other risk factors and clinical preference, the dose could be increased to 162 mg nightly.³⁴ This is supported by the 2018 British Transplantation Society/Renal Association UK guidelines for LKD.³⁷

Do LDs Have a Higher Risk of Postpartum Depression?

The prevalence of postdonation depression ranges between 5% and 23%^38,39 as compared with 10.3% for adult women in the general US population (and 6.2% for men).⁴⁰ Risk factors of postdonation depression include history of predonation depression, greater financial burden, younger age, recipient graft failure or death, single marital status, and short-term medical complications.^39,41

Postpartum depression affects 7%–15% of women worldwide and is a leading cause of maternal mortality and morbidity. Preeclampsia is associated with a higher risk of postpartum depression and more severe symptoms.³² It is unknown whether LKDs have a higher risk of postpartum depression compared with nondonors. However, because LKDs have a slightly higher risk of preeclampsia, and preeclampsia has recently been associated with postpartum depression, it is possible that LKDs may have a slightly higher risk of postpartum depression. Until further data are available, it is recommended that women donors be advised on this possibility so that they can be aware of this risk and seek care early on.

What is the Financial Burden of Becoming Pregnant after Living Donation?

It has been well established that LDs often encounter financial struggles after donation.^42,43 LDs require 4–8 weeks of recovery after surgery and time off work, maybe without pay, all of which may result in lost income. This interruption in employment or loss of employment may lead to loss of work-related benefits, including health insurance.^44,45 A Canadian study looking at the economic burden of LKDs found that almost all LKDs (96%) experience economic consequences, with 94% reporting travel costs and 47% reporting lost pay.⁴⁶ This is particularly alarming noting Canada is a one-payer health system.

Prenatal and postpartum care is essential to prevent pregnancy-related complications and improve maternal and fetal outcomes. It is well known that economic barriers can limit access to health care in general, and pregnancy is no exception. In a cross-sectional study of 3509 peripartum women, health care unaffordability (60%), general financial stress (54%), and unmet health care needs (24%) were commonly reported.⁴⁷ Pregnancy-related complications can increase the cost of medical care.⁴⁸ There are no data regarding the financial implications of pregnancy care in LDs. Taken together, there is a concern that women LDs may suffer financial hardship that would preclude them from getting the care they need in general, but particularly during their pregnancy to ensure a healthy pregnancy and baby. This is another important topic for future data collection.

What is the Available Evidence for LLDs?

The data are scarcer for LLDs. A multicenter, survey-based, retrospective cohort study examined pregnancy-related outcomes in 151 women LLDs aged 18–50 years who donated between 1998 and 2016.⁴⁹ Significantly higher rates of cesarean section (35.4% after donation versus 19.7% before donation) and elevated liver enzymes (3.5% after donation versus 0% before donation) were observed in LLDs conceiving after donation compared with candidates who conceived before donation.⁴⁹ The reasons for this were unclear. There were no significant differences between these subpopulations in rates of preterm birth; birth defects; intrauterine growth restriction; coagulopathy; hemolysis, elevated liver enzymes, and low platelet syndrome; preeclampsia; GDM; and GHTN. No episodes of acute liver failure were reported. Although the median time from liver donation to live birth was 4.8 years, the earliest birth occurred 11 months after donation. From these limited data, it appears that pregnancies in LLDs can progress without a significantly increased likelihood of complications and result in live births at rates similar to the general population. Acknowledging the lack of data in LLDs, it is our opinion that LLDs should consider the use of aspirin starting at 12 weeks' gestation to mitigate any preeclampsia risk.

Liver regeneration is slower for women donors, reaching 79.8% of predonation liver volume at 1 year.⁵⁰ Because most of the liver regeneration happens in the first 3 months after donation but continues throughout the first year,⁵¹ we recommend to delay conception for at least 6 months after donation. This important topic is suitable for information gathering, such as in LD registries.

The Path Forward: Barriers and Strategies for the Creation of a LD Registry

Current State of LD Registries

Successful models to capture long-term information on LD outcomes exist in some countries, particularly those with universal health care systems, such as Switzerland, Norway, Australia, and New Zealand (Table 3).^59,63,64 In the United States, transplant centers are mandated to report some baseline information on all LDs (kidney and liver) to the OPTN and limited follow-up information to 2 years after donation,⁵⁶ but importantly, information related to reproductive health and pregnancy is not included. The United States has lacked a long-term donor registry, but recently the Health Resources and Services Administration, US Department of Health and Human Services, established the Living Donor Collective, an effort to create a lifetime registry for all LD candidates evaluated at a US transplant center administered by the Scientific Registry of Transplant Recipients.^52,53 Under this model, transplant centers register LD candidates and the Scientific Registry of Transplant Recipients is responsible for follow-up. In the event that a LD candidate is fully approved for donation but for whatever reason does not proceed with donation (e.g., the recipient receives another organ or becomes too sick for transplantation), the candidate becomes a nondonor control. Starting data collection upstream with LD candidates is designed to (1) help identify barriers to and disparities in LD and (2) capture data on nondonor controls, to help quantify risks attributable to donation, which may inform strategies for risk prevention or mitigation. The project began as a pilot and is now expanding with a goal of universal national participation.⁵⁴ Although the model of voluntary participation faces many challenges,⁶⁵ efforts to construct a national US LD registry are long overdue.⁶⁶ Discussions of the content of follow-up and information of interest most important to LDs, families, and other stakeholders are underway.⁶⁷

Table 3.

Current living donor follow-up registry structure and data

Registry	Structure of Follow-Up	Time Line of Follow-Up	Demographics
The SRTR Living Donor Collective: A Scientific Registry for LDs52	• SRTR medical and psychosocial surveys • Contact from SRTR through mail, social media, phone • Long- term data follow-up linked to the Centers for Medicare & Medicaid Services, OPTN transplant registry, Centers for Disease Control and Prevention, National Center for Health Statistics, and National Death Index	• Registers LD candidates • Follows both candidates and those who donate • 1 yr, then plan approximately every 1–2 subsequent years	• Pilot phase; ten kidney and six liver centers • 2455 kidney donor candidates registered by 2020, including53,54  • 22.1% aged 18–34  • 35.9% aged 35–49  • 61.4% female  • 72.4% White  • 11.9% Black  • 5% Asian  • 0.7% Hispanic • 398 liver donor candidates registered by 2020, including55  • 34.7% aged 18–34  • 46.2% aged 35–49  • 53.5% female  • 89.4% White  • 2.3% Black  • 1.8% Asian  • 6.3% multiracial  • 0% Hispanic • Follow-up is being designed, with stakeholder input
US OPTN Living Donor Follow-up Form56	• Transplant centers collect follow-up and report to the OPTN	• 6 mo • 1 yr • 2 yr	• Among 64,236 US kidney LDs from 2011–202157   27.7% aged 18–34   39.8% aged 35–49   63.3% female   70.3% White   9.5% Black   4.2% Asian   14.6% Hispanic • Among 4006 US liver LDs from 2011–2021   46.8% aged 18–34   39.9% aged 35–49   54.6% female   78.3% White   4.3% Black   3.1% Asian   13.0% Hispanic • No information on reproductive health is collected at baseline or in follow-up
EULID Registry Data recommendations58	• Medical and/or psychosocial follow-up	• Annual donor checkups • Short- and long-term medical follow-ups • Mandatory short-term psychosocial follow-ups; long-term follow-ups for donors with high medical or psychological stress levels
SOL-DHR59	• Follow-up reporting • Follow-up questionnaire • SF-8 form and social status questionnaire	• 1 yr • 3 yr • 5 yr • 7 yr • 10 yr • Biennial after 10 yr	• 2620 LKDs as of June 30, 202260  • 64.3% female  • 53 yr median age  • 52.5 yr mean age • 65 LLDs as of June 30, 202260  • 56.9% female  • 38 yr median age  • 39.8 yr mean age
ANZADATA Long Term Follow-up (yearly) Form61	• Reporting by transplant hospital or current treating nephrologist	• Annually
Scandiatransplant follow-up form62	• Transplant program reports (printed and sent by mail)	• Follow-up appointments at 3, 6, and 12 mo • Nephrologists submit registry forms at 3, 6, 12 mo, yearly for 5 yr, and then every fifth year (about 40%–50% are lost to follow-up after 5 yr)	• Approximately 3000 donors • Approximately 60% female • 45–50 mean age at donation

ANZDATA, Australia and New Zealand Dialysis and Transplant Registry; EULID, Euro Living Donor; LD, living donor; LKD, living kidney donor; LLD, living liver donor; OPTN, Organ Procurement and Transplantation Network; SOL-DHR, Swiss Organ Living Donor Health Registry; SRTR, Scientific Registry of Transplant Recipients.

Potential Strategies to Capture Pregnancy-Related Outcomes

Within existing donor registries, only limited information is gathered on reproductive health or pregnancy-related outcomes. In Norway, pregnancy-related outcomes of LD have been estimated by linking the donor registry to the national pregnancy registry. A retrospective, multi-institution survey of LLDs gathered data from 151 women with 313 pregnancies, representing 151 of 546 (27.6% with contact information and responded), illustrating the challenges in maintaining contact and obtaining survey responses, especially when time has passed since donation.⁴⁹ Some practices and infrastructure from the successful Transplant Pregnancy Registry International project for transplant recipients may be suitable for application to a LD registry.⁶⁸ The Transplant Pregnancy Registry International is a voluntary pregnancy registry that has been collecting pregnancy-related outcome data since 1991 (Table 4).

Table 4.

Surveys and other data collection models

Data Source/Study	Design/Structure of Follow-Up	Sample and Follow-Up	Pregnancy-Related Measures and Key Findings
Multi-Institutional Retrospective Cohort LLDs49	• Model of patient-directed retrospective survey • Six North American transplant centers • Multiple-step effort that included email, phone, or mail contact for participation. Women donors with contact information were sent either a Web-based survey (Qualtrics, Provo, Utah) or hard copy of the survey	• 151/546 representation rate (27.6% with contact information and responded) • Years from first delivery to survey, median (IQR)  • Predonation pregnancies only (n=64): 23.9 (15.0–30.5)  • Postdonation pregnancies only (n=35): 6.6 (3.1–9.4)  • Pregnancies both before and after donation (n=18): 7.0 (4.8–9.0)	• 151 female LDs responded • 313 reported pregnancies • All predonation pregnancies (n=199; pregnancies from 82 donors)  • 68.8% live birth  • 16.6% miscarriage  • 12.6% elective abortion • All postdonation pregnancies (n=114; pregnancies from 53 donors)  • 71.9% live births  • 24.6% miscarriage  • 3.5% elective abortion
Linked health care database in Canada69	• Add as a model of reviewing health care claims	• 85 LKDs matched to 510 healthy controls, identified in transplant and medical claims databases in Ontario, Canada (1992–2010)	• Diagnosis of GHTN or preeclampsia was more common among living kidney donors than among nondonors (occurring in 15 of 131 pregnancies [11%] versus 38 of 788 pregnancies [5%]; OR for donors, 2.4; 95% CI, 1.2 to 5.0; P = 0.01) • Limitations: Measures based on diagnosis and procedure codes lack clinical granularity
TPRI68	• Voluntary registry of SOT recipients that either fathered or had a pregnancy	• Follow up with participants 1 mo after delivery; subsequent follow-up every 1–2 yr or as needed	• Collected data includes complications during pregnancy (preeclampsia, miscarriages, infections), allograft function, fetal outcomes • Findings not applicable (registry of recipients)

CI, confidence interval; GHTN, gestational hypertension; HTN, hypertension; IQR, interquartile range; LD, living donor; LKD, living kidney donor; LLD, living liver donor; OR, odds ratio; SOT, solid organ transplant; TPRI, Transplant Pregnancy Registry International.

Proposed data elements of interest to better characterize pregnancy-related outcomes for LDs include donor demographics, existing diagnosis, kidney function, results of genetic testing, and detailed pre- and postdonation pregnancy history are listed in Table 5.

Table 5.

Proposed data elements for future pregnancy registry of living donors and donor candidates

Demographics

• Demographic/health history questions

Donor evaluation

• Height, weight, BMI

• BP

• Renal function measures (e.g., serum creatine, cystatin C, eGFR, mCrCl, mGFR)

• Urine albumin excretion (kidney donors)

• Liver function tests (liver donors)

• Lipid panel

• Hemoglobin A1c

• Serum uric acid

• Any genetic test results

• Medications

Predonation pregnancy history

• Number of pregnancies

• Age at the time of each pregnancy

• Number of miscarriages

• Age at the time of each miscarriage

• Infertility issues

• Age at the time of infertility diagnosis

• Use of assisted reproductive technologies

• How long before donation was the pregnancy/pregnancies? (donor age at pregnancy)

• Fetal complications during the pregnancy/pregnancies

• Maternal complications during the pregnancy/pregnancies (GHTN, preeclampsia, GDM, thrombosis, coagulopathy, abnormal liver enzymes, acute fatty liver, HELLP, postpartum depression)

• Fetal outcomes of pregnancy/pregnancies (intrauterine growth retardation, preterm birth, birth defects)

• Maternal outcomes of pregnancy/pregnancies

• Delivery outcome (vaginal birth, cesarean birth, abnormal bleeding, length of stay)

• Use of aspirin during pregnancy

Postdonation pregnancy history

• Number of pregnancies

• Age at the time of each pregnancy

• Number of miscarriages

• Age at the time of each miscarriage

• Infertility issues

• Age at the time of infertility diagnosis

• Use of assisted reproductive technologies

• How long after donation was the pregnancy/pregnancies (donor age at pregnancy)

• Fetal complications during the pregnancy/pregnancies

• Maternal complications during the pregnancy/pregnancies (GHTN, preeclampsia, GDM, thrombosis, coagulopathy, abnormal liver enzymes, acute fatty liver, HELLP, postpartum depression)

• Fetal outcomes of pregnancy/pregnancies (intrauterine growth retardation, preterm birth, birth defects)

• Maternal outcomes of pregnancy/pregnancies

• Delivery outcome (vaginal birth, cesarean birth, abnormal bleeding, length of stay)

• Use of aspirin during pregnancy/pregnancies

• Did your transplant team discuss postdonation pregnancy with you?

BMI, body mass index; GDM, gestational diabetes mellitus; GHTN, gestational hypertension; HELLP, hemolysis, elevated liver enzymes and low platelets; mCrCl, measured creatinine clearance; mGFR, measured GFR.

Since the first successful living kidney donation, there have been questions about the long-term effects of donation. Our goal was to highlight the challenges related to pregnancy effects on future health and future pregnancies after donation. The potential donor must be apprised of the risks known and unknown. Although there is paucity of data and of limited quality at times, from that available, there is no absolute contraindication to pregnancy after living donation. It is our duty to further the science so that donors have the best knowledge to make an informed decision about their donation and future health. This group of experts wholeheartedly supports the formation of a registry for potential donors and long-term follow-up of those who donate.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C33.

Funding

K.L. Lentine: Mid-America Transplant/Jane A. Beckman Endowed Chair in Transplantation. S. Shah: National Institutes of Health (1K23HL151816-01A1).

Author Contributions

Conceptualization: Lisa Coscia, Goni Katz-Greenberg, Ana P. Rossi.

Data curation: Carla W. Brady, Christina Doligalski, Roxanna A. Irani, Krista L. Lentine, Ana P. Rossi.

Investigation: Goni Katz-Greenberg, Krista L. Lentine, Ana P. Rossi.

Methodology: Lisa Coscia, Goni Katz-Greenberg, Ana P. Rossi.

Project administration: Lisa Coscia, Ana P. Rossi.

Resources: Lisa Coscia, Ana P. Rossi.

Supervision: Krista L. Lentine, Ana P. Rossi.

Visualization: Ana P. Rossi.

Writing – original draft: Carla W. Brady, Christina Doligalski, Goni Katz-Greenberg, Krista L. Lentine, Ana P. Rossi.

Writing – review & editing: Carla W. Brady, Lisa Coscia, Christina Doligalski, Roxanna A. Irani, Goni Katz-Greenberg, Krista L. Lentine, Arthur Matas, Ana P. Rossi, Silvi Shah.