The research team, led by investigators from the University of Florida and the University of Birmingham, analyzed data from the Scientific Registry of Transplant Recipients and the UK Transplant Registry, covering 81,729 first liver transplants. Rather than simply comparing raw death rates between men and women, the researchers calculated excess mortality—the difference between the death rate in transplant recipients and the death rate expected in the general population of the same age and sex. This approach matters because men generally die at higher rates than women in the general population, so raw comparisons can obscure important differences.

Excess mortality was substantially larger for female recipients in the first 90 days after transplant. Among women aged 25 to 64, the excess death rate in the first three months was roughly double that seen in male recipients of the same age. The gap was widest among women aged 45 to 64, where the excess mortality in the first 90 days was more than twice that of men. After the first year, however, the pattern reversed, with female recipients showing lower excess mortality than male recipients in most age groups.

The researchers suggest that the poorer condition of female patients at the time of transplant may explain the early disadvantage. Women on the transplant waiting list tend to have more advanced disease at the time they receive a new liver, possibly because they are referred for transplant later in the course of their illness or because disease progression differs between the sexes. Female recipients were also more likely to receive organs from male donors, which previous research has linked to poorer outcomes, although the new analysis found the early mortality gap persisted regardless of donor sex.

Notably, the study found that the direction of the sex difference in mortality changed over time. In the first 90 days, women fared worse; between 90 days and one year, the difference narrowed considerably; and after one year, women generally showed lower excess mortality than men. The researchers suggest that women who survive the critical early period may be a hardier group, having withstood the stresses of transplant surgery and immunosuppression, while men who survive may represent a more fragile subset.

The analysis also revealed that the sex difference in mortality varied by age. Among recipients aged 18 to 24, the early disadvantage for women was particularly pronounced, with excess mortality in the first 90 days more than three times that of male recipients. The researchers suggest that young women may face unique challenges, including autoimmune liver disease, which disproportionately affects young women and tends to progress rapidly.

The study’s findings have implications for transplant practice. The researchers suggest that clinicians should be aware that female recipients may need closer monitoring in the early post-transplant period, and that the timing of transplant referral may need to be reconsidered for women with advanced liver disease. The finding that women show lower excess mortality after the first year suggests that the early disadvantage is not an inherent biological limitation but rather a consequence of differences in disease severity and timing of transplant.

The researchers acknowledge several limitations. The analysis relied on registry data, which may contain coding errors, and the study could not account for all potential confounding factors, including differences in immunosuppression regimens, comorbidities, and socioeconomic status. The researchers also note that the study period spanned more than three decades, during which transplant practice changed considerably, including the introduction of new immunosuppressive drugs and changes in organ allocation policies.

Despite these limitations, the study provides a comprehensive picture of sex differences in liver transplant outcomes across a large, diverse population. The finding that the direction of the sex difference in mortality changes over time highlights the importance of considering the full post-transplant trajectory rather than focusing on any single time point. The researchers suggest that future studies should investigate the mechanisms underlying the early disadvantage for women, including differences in disease severity at transplant, surgical complications, and immune responses to the new liver.

The study drew on two of the largest transplant data resources in the world. The Scientific Registry of Transplant Recipients captures information on all donors, waitlisted candidates, and recipients in the United States as reported to the Organ Procurement and Transplantation Network, with oversight from the Health Resources and Services Administration. Death ascertainment in the SRTR is particularly robust because it is linked to the U.S. Master Death File, meaning that even patients lost to routine follow-up have deaths captured, resulting in essentially no loss to follow-up for the mortality outcome. The international Collaborative Transplant Study, by contrast, collects data from more than 400 centers across 42 countries, although only 26 countries reported liver transplant data during the observation window. In the CTS, deaths are reported annually by participating centers, and patients lost to follow-up are censored, a structural difference between the two datasets that the investigators had to address in their analysis.

To harmonize the two cohorts, the team excluded countries contributing fewer than 100 transplants or fewer than 10 patients under observation at ten years, a threshold that removed only about 2 percent of CTS-reported transplants. U.S. recipients were excluded from the CTS cohort to prevent duplication with the SRTR. Follow-up for all patients extended through the end of 2019, a cutoff chosen deliberately to avoid the confounding effects of the COVID-19 pandemic, which increased mortality among transplant recipients and affected men and women differently.

The analytic strategy reflected the growing recognition that sex effects in transplantation are not uniform across the lifespan. Recipient current age was treated as a time-varying variable and divided into five categories reflecting major phases of biological development: pre-pubertal children aged 0 to 12, reproductive-age recipients aged 13 to 24, adults aged 25 to 44, adults aged 45 to 59, and those aged 60 and older. Preliminary models showed nearly identical relative excess risk estimates for the two oldest categories, so the investigators merged them into a single group of recipients aged 45 and older. This design choice matters because the phenotypic expression of sexual dimorphism changes with sexual development and with aging, and prior work in kidney and heart transplantation has demonstrated that the magnitude and even the direction of sex differences in outcomes shift substantially with age. No earlier study of liver transplant mortality had examined age as an effect modifier.

Donor sex was handled with equal care. Recipients were classified into four donor-recipient sex combinations—female donor with female recipient, female donor with male recipient, male donor with female recipient, and male donor with male recipient—and an interaction term between these combinations and recipient current age was included in every model. This was motivated by earlier findings that both donor sex and recipient age modify the association between recipient sex and outcomes in kidney and heart transplantation, and that similar modification occurs for graft loss in liver transplantation.

The choice of excess mortality as the outcome deserves emphasis. Because men die at higher rates than women in the general population worldwide, a simple comparison of observed death rates between male and female recipients can be misleading. By comparing the observed mortality of transplant recipients against the mortality expected in sex- and age-matched members of the general population, the relative survival framework isolates the mortality burden attributable to transplantation itself and allows a fairer comparison between the sexes.

Death after liver transplant is only occasionally explained by the graft itself. In the early post-transplant period, prior studies report that just 5 to 9 percent of deaths are attributable to graft failure, with infection accounting for roughly 28 percent of deaths and cardiovascular disease about 16 percent. Beyond the early period, 80 percent or more of deaths stem from causes other than graft failure. One American study found sex differences in graft failure rates that varied by recipient age and donor sex, but since graft failure and overall mortality do not necessarily follow the same patterns, the investigators could not assume that sex differences in excess mortality would mirror differences in graft outcomes.

The analysis was restricted to first liver-only transplants from deceased donors, with observation censored at re-transplant, at the end of the study period, or at the end of follow-up. This restriction reflects a practical methodological point: donor characteristics change with subsequent transplants, so including re-transplants would complicate the comparison of donor-recipient sex combinations. The scope of the work was large, encompassing 218,429 first liver transplant recipients transplanted between January 1, 1988 and December 31, 2019, with models fitted separately in the SRTR and CTS cohorts and then combined through a two-stage individual patient data meta-analysis.

The headline findings sharpen the clinical picture. Within the first three months after transplant, female recipients aged 25 and older showed significantly higher excess mortality than their male counterparts regardless of donor sex, and females aged 13 to 24 had significantly higher excess mortality when their donor was male. After the third month, however, the picture shifted: female recipients aged 0 to 12 showed significantly lower excess mortality regardless of donor sex, and among adults aged 25 to 44 the female advantage reached statistical significance when the donor was female. Taken together, the results suggest that the early disadvantage experienced by adult female recipients is concentrated in the immediate perioperative window, while longer-term survival among recipients who weather that period is equal or better for women across much of the age range.

Subject of Research: Sex differences in liver transplant mortality

Article Title: Differences in excess mortality by recipient sex after liver transplant

Article References: Grinspan, L. T., Zhang, X., Dahhou, M., Süsal, C., Bernd, D., Melk, A., Vinson, A., & Foster, B. J. (2026). Differences in excess mortality by recipient sex after liver transplant. Transplant International, 39, Article 16922. https://doi.org/10.3389/ti.2026.16922

Image Credits: AI Generated

DOI: 10.3389/ti.2026.16922

Keywords: liver transplant, excess mortality, sex differences, transplant outcomes, donor sex, post-transplant mortality, Differences, excess, mortality, recipient, liver, transplant