Risk factors affecting mortality in pediatric heart transplantation: A comprehensive review of pre- and post-transplant contributors

Abstract

Pediatric heart transplantation (HT) has transformed outcomes for children with end-stage heart failure. Despite advances in surgical techniques and immunosuppressive strategies, mortality remains influenced by numerous risk factors. This review consolidates current literature on pre- and post-transplant variables affecting mortality in pediatric HT, focusing on donor, recipient, and environmental contributors. Pertinent adult studies are also incorporated to highlight overlapping considerations. Recognition of these factors is critical to improving graft survival and long-term outcomes. Key pre-transplant elements include repeated sternotomies, high pulmonary vascular resistance, and extremes of body mass index, while post-transplant issues such as infection, rejection, and cardiac allograft vasculopathy (CAV) remain pivotal. Social determinants of health further modulate survival, reflecting the multifaceted nature of pediatric HT outcomes. By synthesizing existing data, this review aims to provide a framework for identifying high-risk profiles in pediatric HT recipients.

Heart transplantation is a life-saving treatment for children with end-stage heart failure, significantly improving both survival and quality of life. Since pediatric heart transplantation became widely accepted in the 1980s,¹ advances in surgical techniques, immunosuppression protocols, and perioperative care have further enhanced patient outcomes.

Despite these improvements, a range of pre- and post-transplant risk factors continues to limit overall survival. Pediatric recipients face unique challenges compared to adults due to developmental, immunological, and anatomic differences. For example, conditions such as congenital heart disease, elevated pulmonary vascular resistance, and pre-transplant sensitization elevate perioperative risk, while post-transplant complications—including infections, rejection episodes, and cardiac allograft vasculopathy (CAV)—as well as social determinants of health, substantially influence long-term outcomes.

This review is designed for pediatric heart transplant teams involved in transplant evaluation, care, and follow-up. It supports informed discussions with families by offering evidence-based insights into risk factors affecting outcomes. While risk tolerance and management vary by center, a shared understanding of modifiable and non-modifiable risks can enhance decision-making and transparency. Synthesizing pediatric and select adult data, this review offers a practical framework for identifying and contextualizing high-risk features in children undergoing heart transplantation.

Pre-transplant risk factors

Congenital heart disease as an indication for transplant

Over the past decade, congenital heart disease (CHD) has emerged as an increasingly common indication for pediatric heart transplantation (HT).² CHD patients experience significantly higher waitlist mortality than cardiomyopathy patients, with single-ventricle CHD patients facing the longest waitlist times and highest early post-transplant mortality.³ By 3 years post-transplant, overall survival is 88% for cardiomyopathy patients, compared to 79% for those with CHD.⁴ Increased surgical complexity from prior palliative procedures, altered anatomy, and prolonged cardiopulmonary bypass (CPB) times further contribute to early post-transplant mortality in CHD patients. These findings, while based on adult congenital heart disease cohorts, offer insight into transplant risk among adolescents with similar anatomic complexity.5, 6

In patients with single ventricle CHD and failing Fontan physiology, hepatic dysfunction can progress to Fontan-associated liver disease (FALD), characterized by nodular transformation, portal hypertension, and synthetic dysfunction. Those with significant hepatic compromise may require combined heart-liver transplantation, though institutional practices vary.⁷ Furthermore, Fontan patients have a significantly higher post-transplant infection risk (54% vs. 27% in cardiomyopathy), driven by pre-transplant factors and an altered immunophenotype with reduced naïve T-cell populations and impaired immune recovery.8, 9

Prior sternotomy

Number of prior sternotomies has been shown in adult populations to increase morbidity and mortality in heart transplant recipients due to surgical complexity, prolonged CPB times, and a heightened risk of complications. These patients often experience dense adhesions, increased bleeding risk, and longer operative times, leading to higher intraoperative blood product utilization and a greater likelihood of early graft dysfunction.10, 11 Each additional prior surgery further compounds these risks, with prior sternotomy identified as an independent predictor of lower survival.¹²

Recipient age

Age at transplantation significantly influences both early and long-term survival outcomes. Infants have the highest mortality rate in the early post-transplant period. However, those who survive beyond the first year after HT achieve the best long-term outcomes of any age group, with a transplant half-life approaching 20 years.¹³ In contrast, children transplanted between 11 and 17 years of age exhibit a significantly lower overall survival post-transplant, specifically during the early post-transplant period.¹⁴

Freedom from CAV varies by age at transplant, with infants having the highest freedom and adolescents (11–17 years) the lowest. However, once diagnosed with CAV, survival rates are similar across all age groups.¹⁴

Donor–recipient age mismatch

Donor–recipient age mismatch has been associated with increased post-transplant mortality, particularly in adolescent recipients. Receiving a heart from a donor more than 5 years older is linked to reduced survival, with the greatest risk observed in adolescent recipients receiving hearts from donors over 25 years old.¹⁵ This group also experiences higher rates of CAV, a leading cause of late graft failure.¹⁵ Similarly, donor age over 40 years in adult congenital heart disease patients was associated with decreased 10-year survival.¹⁶ Donor-recipient age mismatch is linked to reduced post-transplant survival, but its independence from size mismatch remains unclear in pediatric cohorts.

Blood type mismatch

ABO-incompatible (ABOi) heart transplantation has significantly expanded the pediatric donor pool, particularly for infants. Large registry data confirm that ABOi transplants in infants achieve comparable one-year survival to ABO-compatible transplants, with no significant differences in rejection incidence, freedom from CAV, or post-transplant hospital stays.17, 18 Recent evidence suggests that ABOi heart transplantation may be feasible in select older pediatric patients, challenging previous concerns about isohemagglutinin development. A 2019 study showed that ABOi transplants in children over 2 years of age can achieve survival outcomes comparable to ABO-compatible transplants, supporting broader consideration of this approach in carefully selected cases.¹⁹ Notably, ABOi recipients experienced fewer severe bacterial infections, particularly with polysaccharide-encapsulated bacteria, which may share immunological properties with blood group antigens, suggesting a potential immunologic advantage in infection susceptibility.¹⁸

Malnutrition and body mass index

Malnutrition plays a crucial role in pediatric heart failure, significantly impacting outcomes after heart transplantation. Studies have shown that higher weight-for-age z-scores are independently associated with improved survival, whereas poor preoperative growth is linked to increased post-transplant mortality, earlier episodes of rejection, reduced graft survival, and higher rates of graft vasculopathy. Notably, poor growth itself was an independent risk factor for post-transplant mortality.²⁰

Body mass index (BMI) also plays a role in pediatric HT outcomes, though the data are conflicting. A 2018 study found that post-transplant survival was lower in overweight and obese recipients (BMI ≥ 25 kg/m²) compared to those with normal BMI.²¹ Additionally, overweight and obese recipients were more likely to develop diabetes and experience rejection requiring hospitalization after transplant.²¹ Analyses of the United Network of Organ Sharing (UNOS) database identify post-transplant obesity (BMI ≥ 30 kg/m²) and underweight status (BMI < 18.5 kg/m²) as independent predictors of age- and sex-specific mortality,²² with BMI ≥ 35 kg/m² further associated with increased post-transplant mortality in adult recipients.²³ Other studies have not consistently demonstrated a direct relationship between BMI at the time of transplant and survival outcomes in pediatric HT recipients, highlighting the need for further research.²⁴ Additionally, ethical concerns have been raised regarding the use of BMI as a strict exclusion criterion for transplantation, as this practice may disproportionately impact certain populations and exacerbate disparities in access to care.²⁵ Optimization of nutritional status, including targeted growth or weight loss, is generally recommended, as improved weight-for-age z-scores are independently associated with better post-transplant survival.

Mechanical ventilation prior to transplant

Mechanical ventilation before heart transplantation is a significant risk factor for worse post-transplant outcomes. Intubation prior to HT is associated with a significant decrease in one-year survival.²⁶ The duration of ventilation also impacts outcomes, as patients ventilated for ≤1 week have survival rates comparable to non-ventilated patients, whereas ventilation for more than one week is linked to a significantly higher mortality risk.²⁷

Pulmonary hypertension

Pulmonary hypertension presents a significant challenge in pediatric HT, particularly due to the increased afterload placed on the transplanted right ventricle. While historically considered a contraindication, recent findings suggest that elevated pulmonary vascular resistance (PVR) is not always associated with worse early survival.²⁸ Patients with an indexed PVR between 6 and 9 Wood units do not have significantly higher 30-day mortality, and even those with PVR >9 achieve 78.9% survival at 30 days.²⁸ In modern cohorts, primary pulmonary hypertension patients demonstrate 93% 1-year survival and 67% 5-year survival.²⁹

Pre-sensitization

Pre-sensitization, indicated by elevated panel reactive antibodies (PRA), can also pose significant challenges in pediatric HT. Sensitization often results from prior cardiac surgeries, homograft exposure, blood transfusions, or mechanical circulatory support.³⁰ The presence of anti-human leukocyte antigen (HLA) antibodies—particularly against HLA-A—has been associated with increased severity of primary graft dysfunction in adult HT recipients, underscoring the importance of pre-transplant immunologic risk stratification.³¹

Sensitization, defined as a PRA ≥ 10%, affects 15–30% of pediatric heart transplant candidates, with rates rising in recent years. Patients with CHD, particularly adolescents, are more likely to be sensitized than those with cardiomyopathy.

While data on the impact of elevated PRA on post-transplant outcomes is conflicting, International Society for Heart & Lung Transplantation (ISHLT) registry findings suggest no association with long-term survival. However, smaller studies have reported higher overall mortality in sensitized recipients, especially those with a positive retrospective or prospective crossmatch. Notably, a study from the Pediatric Heart Transplant Society (PHTS) found that 6-month survival was lower (77% vs. 93%) in patients with PRA ≥ 50%, though those with negative prospective crossmatches had outcomes comparable to non-sensitized recipients.³² Registry data further show that a positive T-cell complement dependent cytotoxicity crossmatch doubles the risk of treated rejection in the first year and increases the risk of death or allograft loss by 50%, whereas a positive T-cell Flow crossmatch is not associated with worse outcomes.³³

Mechanical circulatory support

Mechanical circulatory support, including extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs), serves as a critical bridge to heart transplantation (HT) in children with decompensated heart failure. However, both strategies carry significant risks that impact post-transplant survival.

ECMO is associated with substantially increased post-transplant mortality, with studies showing a significantly higher risk of in-hospital death compared to non-supported patients.29, 34 ECMO recipients also experience longer intensive care unit stays and increased perioperative complications.26, 35 Given these risks, ECMO remains a high-risk bridge to transplant, often reserved for critically ill patients with no alternative support options.

VADs offer a more stable bridge to transplant and are associated with better post-transplant survival compared to ECMO.³⁴ However, complications such as thrombosis, bleeding, and infections remain significant concerns. Neurologic and renal complications are particularly notable, with acute kidney injury (AKI) occurring in up to 50% of VAD-supported patients.³⁶ Stroke incidence varies by device type, with pulsatile-flow VADs carrying a lower stroke rate (6.4%) compared to continuous-flow devices (11.1%).³⁷

Donor factors: Cocaine use and smoking history

Donor factors, including substance use history, are routinely assessed for their impact on pediatric HT outcomes. The effect of donor cocaine use is conflicting: while large registry studies show no significant differences in survival, rejection, or cardiac allograft vasculopathy,³⁸ other studies suggest a modest increase in long-term mortality.³⁹ These discrepancies may stem from variations in donor selection, reporting, and population-specific risks. As such, donor cocaine use is not an absolute contraindication but requires careful evaluation of donor quality and associated risks.

While donor cocaine use may pose specific risks for long-term survival, other lifestyle factors such as smoking history have been more consistently associated with higher post-transplant mortality and graft dysfunction. ISHLT registry data demonstrate significantly worse 5-year survival (73.9% vs. 76.7%) and higher graft failure rates (27.0% vs. 23.6%) in adult heart recipients from donors with a smoking history.⁴⁰

Donor ischemic time

Donor ischemic time—the interval from donor aortic cross-clamp to recipient reperfusion—is a key determinant of morbidity and mortality in pediatric HT. Ischemic durations of ≥4 h are associated with significantly lower unadjusted 30-day and overall survival compared to shorter durations.⁴¹ Multivariable analyses further show that prolonged ischemic time independently increases the risk of 1- and 5-year mortality, especially in infants, though it is not associated with the development of CAV or renal dysfunction at 5 or 10 years. Interestingly, among patients with congenital heart disease, ischemic time was not linked to overall survival.⁴¹ Additionally, functional recovery may be impacted by ischemic duration; in a prospective cohort, patients with ischemic times >180 minutes demonstrated higher peak VO₂ but shorter cardiopulmonary exercise durations, suggesting reduced endurance despite preserved oxygen uptake.⁴²

Post-transplant risk factors

Infection

Bacterial

Infection remains a leading cause of early mortality after pediatric HT,⁴³ with bacterial infections accounting for over 40% of severe post-transplant infections. The highest risk occurs within the first month post-transplant, with bloodstream infections affecting nearly 25% of recipients, often due to multidrug-resistant pathogens. Coagulase-negative staphylococci, Enterobacter species, and Pseudomonas species are the most common early post-transplant pathogens, while Streptococcus pneumoniae and Haemophilus influenzae emerge later. Risk factors for bacterial infection include younger age, mechanical ventilation, and ECMO support at the time of transplant. Mortality following bacterial infection remains high at 33.8%, with prior cardiac surgery and infections at multiple sites identified as independent predictors of death.⁴⁴ ECMO-bridged recipients face a 30–40% higher incidence of severe infections, leading to worse survival outcomes.⁴⁴

Viral

Cytomegalovirus (CMV) remains a significant cause of morbidity in transplant recipients, often leading to direct viral injury of graft tissue, promoting secondary infections, and has immunomodulatory effects that contribute to rejection, including both cellular and antibody-mediated types. Induction immunosuppressive therapy does not appear to significantly impact CMV infection risk in pediatric heart transplant recipients, as CMV infection rates were similar between those receiving anti-thymocyte globulin (36%) and basiliximab (28.3%), with no significant differences in CMV viremia or CMV-positive tissue biopsy incidence.⁴⁵ Epstein–Barr virus (EBV) also poses a significant risk following pediatric HT due to its role in the development of post-transplant lymphoproliferative disease (PTLD), a serious complication addressed in detail below.

Rejection

Rejection remains a major cause of graft loss and mortality following pediatric HT. Acute rejection includes cellular rejection (ACR), antibody-mediated rejection (AMR), and mixed rejection, with ACR affecting up to 30% of pediatric recipients in the first year.⁴ AMR, though less common, is associated with a higher risk of graft failure and a significant increase in long-term mortality.⁴⁶ In a large registry analysis, AMR was found in 37% of pediatric HT recipients with biopsy-confirmed rejection and occurred significantly earlier than ACR, with a median onset of 0.11 years post-transplant versus 0.29 years for ACR.⁴⁶ Early rejection episodes significantly worsen long-term survival, emphasizing the need for early detection and aggressive management.⁴ Survival following AMR in the first-year post-transplant was lower compared to ACR-only rejection,⁴⁷ and predictors of graft loss after AMR included younger age at HT, congenital heart disease, and rejection with hemodynamic compromise.⁴⁶

Patients with mixed rejection have significantly worse 5-year survival (46.2%) compared to those with ACR (69.8%) or AMR (80.0%) alone, highlighting its severe long-term impact.⁴⁸ While freedom from CAV was similar between patients with and without recurrent rejection, graft survival was significantly worse in those experiencing multiple rejection episodes, particularly those with recurrent AMR.⁴⁸

Post-transplant lymphoproliferative disease

Post-transplant lymphoproliferative disorder (PTLD) remains the most common post-transplant malignancy and a major barrier to long-term survival following pediatric heart transplantation. PHTS and ISHLT datasets have demonstrated an overall freedom from PTLD of 98.5% at 1 year, 94% at 5 years, and 90% at 10 years post-transplant, with 97% of all malignancy events classified as PTLD.⁴⁹ Strong risk factors include donor EBV-positive/recipient EBV-negative (D+R–) mismatch and recipient age between 1 and 9 years, with nearly 25% of D+R– recipients aged 4−7 years developing PTLD in earlier eras. However, risk has decreased over time, likely due to improved surveillance and immunosuppression strategies. A more recent prospective multicenter study confirmed D+R– status as the strongest independent predictor of PTLD, with most cases presenting within 6 months of a solid-organ transplant and more severe histologic subtypes occurring predominantly in non-liver recipients aged ≥5 years.⁵⁰

Cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV) is a progressive coronary vascular disease characterized by diffuse intimal thickening and fibrosis, making it a leading cause of late graft failure and mortality in pediatric heart transplant recipients.⁵¹ Several risk factors contribute to CAV development, including recurrent rejection,⁴⁷ donor-specific antibodies,⁴⁶ CMV infection,⁵² and donor age.⁵²

Long-term freedom from CAV declines over time, with rates of 97% at 3 years post-transplant, decreasing to 67.9% at 15 years and 52.0% at 20 years.⁵¹ Once CAV develops, outcomes worsen significantly—5-year graft survival after diagnosis is just 58%, with even poorer survival (30%) when CAV is detected after symptoms appear, compared to 62% when identified through routine angiography.⁵³ While CAV was historically linked to a 10-fold increase in mortality, advancements in early detection, immunosuppressive therapy, and statin use have helped mitigate its impact in recent years.⁵²

End-organ dysfunction

Renal dysfunction is a significant complication following pediatric HT, contributing to increased morbidity and mortality. Acute kidney injury (AKI) occurs in up to 72% of recipients within the first week post-transplant, with severe AKI requiring dialysis in 7% of cases.54, 55 Beyond the immediate post-transplant period, AKI is a strong predictor of long-term kidney dysfunction, with non-recovery from AKI leading to chronic kidney disease (CKD) in up to 18% of pediatric HT recipients.⁵⁴ By 10 years post-transplant, severe renal dysfunction occurs in 2.4% of recipients transplanted as infants, 4% of those transplanted at ages 1–5, 11% at ages 6–10%, and 14% at ages 11–17, showing an age-related increase in risk. A similar trend is seen in freedom from renal replacement therapy.⁵⁶ Risk factors for AKI and subsequent CKD include longer cardiopulmonary bypass times, elevated central venous pressure, and pre-existing renal impairment.³⁴

Based on the UNOS database, among all pediatric HT recipients, 3.4% were waitlisted for a kidney transplant and among those, 70% received a kidney transplant and 18% died on the waitlist.⁵⁷

In pediatric HT recipients with Fontan physiology, liver dysfunction often occurs due to long-standing venous congestion, leading to FALD. Although HT improves hemodynamics, cirrhosis often persists. In a multicenter study, fibrosis was not associated with increased post-transplant mortality, with some demonstrating improved imaging and laboratory values over time.⁷

Social determinants of health

Social determinants of health significantly influence post-transplant survival, impacting disparities in healthcare access, socioeconomic status (SES), and medication adherence. Lower SES is associated with worse post-transplant outcomes, primarily due to higher rates of late rejection, limited access to specialized care, and increased medication nonadherence.⁵⁸ Regional variations in survival further compound disparities, with children in lower-income areas experiencing higher waitlist mortality and worse post-HT survival.⁵⁸

Nonadherence to immunosuppressive therapy remains a leading contributor to graft loss, with adolescents being particularly vulnerable due to developmental challenges, peer pressure, and reduced family support.⁵⁹ Studies indicate that adolescents transitioning to self-care experience higher rates of late rejection compared to younger pediatric recipients, although precise rejection rates vary across populations.⁶⁰

Racial and ethnic disparities persist in pediatric HT, with minority children experiencing higher waitlist mortality and reduced long-term survival.⁶¹ Additionally, barriers such as financial constraints, transportation issues, and gaps in health literacy disproportionately affect underserved populations, further impacting adherence to post-transplant regimens.⁵⁹

Recent systematic reviews confirm that factors such as household income, parental education level, and neighborhood disadvantage significantly correlate with post-transplant outcomes. Addressing these disparities through targeted interventions remains essential for improving equity in pediatric HT.⁶²

Conclusion

Pediatric heart transplantation significantly improves survival for children with end-stage heart failure, yet substantial risks remain. Pre-transplant factors such as repeated sternotomies, pulmonary hypertension, malnutrition, and sensitization require meticulous risk stratification and individualized management. Post-transplant complications—including infection, rejection and CAV—remain major contributors to morbidity and mortality and are further compounded by socioeconomic disparities and adherence challenges. Integrating multidisciplinary teams (cardiology, immunology, infectious disease, nutrition, and mental health) is essential to address these complex issues. Experienced pediatric heart transplant centers often integrate institutional protocols and multidisciplinary expertise to proactively manage high-risk candidates—such as implementing tailored nutritional rehabilitation or early VAD strategies—to optimize outcomes and mitigate complications across the transplant timeline. Continued advancements in diagnostics, immunosuppressive regimens, and donor organ preservation, as well as ongoing research and interdisciplinary collaboration, are critical to improving both survival and quality of life for pediatric HT recipients.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.