Rutger A. Middelburg
Men who received red blood cell transfusions from women who had ever been pregnant appeared to have an increased risk for death, according to results of a large, retrospective study published in JAMA.
Female recipients did not face a similar risk, researchers noted.
“Six years ago we found transfusions of red blood cells from female donors to be associated with increased mortality among male recipients, especially when aged younger than 50 years,” Rutger A. Middelburg, PhD, assistant professor of clinical transfusion research at Sanquin Research in Leiden, the Netherlands, told HemOnc Today. “This was an unexpected observation and we considered the probability of a false-positive finding (ie, a chance association) to be relatively high.”
Based on these findings, researchers started a follow-up study that had two main objectives.
“First, we wanted to confirm our findings in an independent and much larger cohort,” Middelburg said. “Second, because some complications of blood transfusion are known to be related to pregnancy history of the donor, we wanted to study a possible relationship with previous pregnancy of the blood donors.”
Transfusion of red blood cells is among the most commonly performed procedures in hospitals. Transfusion-related acute lung injury is the most common cause of transfusion-related deaths and has been shown to be associated with transfusions from female donors, specifically from those with a history of pregnancy.
The analysis included data from 31,118 patients (median age, 65 years; interquartile range, 42-77; 52% women) from six major Dutch hospitals who received 59,320 red blood cell transfusions exclusively from one of three types of donors — 88% men, 6% previously pregnant women and 6% never-pregnant women — from May 30, 2005, to Sept. 1, 2015.
All-cause mortality during follow-up served as the main outcome. Researchers compared outcomes following red blood cell transfusions from ever-pregnant or never-pregnant women, with transfusions from male donors.
Researchers reported 3,969 deaths — for a 13% mortality rate — among the entire cohort.
Male recipients of red blood cell transfusions had higher all-cause mortality rates per 1,000 person-years when they had an ever-pregnant vs. male donor (101 vs. 80; time-dependent “per-transfusion” HR for death = 1.13; 95% CI, 1.01-1.26). This risk increased among men aged 18 to 50 years (HR = 1.43; 95% CI, 1.13-1.82).
However, the difference in risk was not statistically significant when researchers compared male recipients with never-pregnant vs. male donors (78 vs. 80; HR = 0.93; 95% CI, 0.81-1.06).
Among female recipients of red blood transfusions, mortality rates did not significantly differ with ever-pregnant vs. male donors (74 vs. 62; HR = 0.99; 95% CI, 0.87-1.13), nor with never-pregnant vs. male donors (74 vs. 62; HR = 1.01; 95% CI, 0.88-1.15).
“We found transfusion of red blood cells from previously pregnant donors to be associated with about 1.5 times increased mortality of male recipients younger than 50 years, compared with transfusion of red blood cells from male donors,” Middelburg said. “The risk remained increased for many years after transfusion. No such increase was observed for female recipients or for male recipients over 50 years.”
Immunologic changes occurring during pregnancy and differences in iron status between ever-pregnant female donors and male donors could serve as mechanisms for the increased mortality among male recipients.
“All data until now seem to point toward an immunological mechanism, and other fields of medical research suggest the male and female immune systems to be different and the female immune system to be permanently altered after pregnancy,” Middelburg said. “However, that doesn’t easily explain why the effect should be limited to relatively young men.”
Researchers acknowledged several limitations of the study, including missing pregnancy status data from 44% of female donors and no information on cause of death.
“My priorities would be to look into more detailed pregnancy histories and causes of death, because those could both provide important clues about the mechanism,” Middelburg said.
Although these results are provocative and could have significant clinical implications, other studies on this topic have reported conflicting results, Ritchard G. Cable, MD, scientific director of the Connecticut region of the American Red Cross Blood Services, and Gustaf Edgren, MD, PhD, senior researcher in the department of medical epidemiology and biostatistics at Karolinska Institute in Stockholm, Sweden, noted in an accompanying editorial.
“The methodology of these types of studies is complex,” Cable and Edgren wrote. “Therefore, alternative explanations for the observed associations should be considered.”
Because red blood cell units from female donors contain about 8% less hemoglobin than those from male donors, patients who receive red blood cell units from women may require additional transfusions. This may affect the rate of censoring in a way that adds bias to the mortality estimates, Cable and Edgren wrote.
The observed findings may not be related to differences in donor red blood cells or iron physiology, but rather an immunologic mechanism based on maternal immunization to paternal antigens, Cable and Edgren added.
“If confirmatory studies in other cohorts demonstrate that a donor’s sex and pregnancy status are associated with posttransfusion mortality, blood centers and transfusion services will need to mitigate this risk,” they wrote. “Potential options could include identification and deferral of high-risk donors, donor-recipient sex matching to avoid increased risk, and mitigation of underlying mechanisms by blood product modifications, such as further reducing residual plasma or lymphocytes.” – by Chuck Gormley
Disclosures: Dutch Ministry of Health, Welfare and Sports funded this study. Middelburg reports no relevant financial disclosures. One author reports fees from Vifor Pharma and advisory roles with Amgen Science and Novartis. Cable and Edgren report no relevant financial disclosures.