Transfusions from females who have been pregnant to males, especially those younger than 50 years, may be associated with increased risk for all-cause mortality, compared with such transfusions to females or with transfusions from women who have never been pregnant to recipients of either sex, according to a study published online on October 17 in JAMA.
Since 2011, several studies have suggested that blood transfusions from women are riskier for recipients than are transfusions from men, and that that risk is greatest from women who have been pregnant. The most common cause of transfusion-related mortality, acute lung injury, is associated with use of plasma-rich products, suggesting an antibody-mediated immune response.
To further examine these associations, Camila Caram-Deelder, a PhD student in the Department of Transfusion Medicine at Sanquin Research, Leiden, the Netherlands, and coworkers analyzed the association between red blood cell transfusion from female blood donors, with and without a history of pregnancy, and mortality among male and female recipients. Sanquin is the source of blood in the Netherlands, and all blood is leukocyte-depleted.
The researchers used a retrospective cohort of people who received their first transfusion between May 30, 2005, and September 1, 2015, at one of six major Dutch hospitals. They considered the age and sex of recipients and the sex and pregnancy history (when known) of donors. Some data were recorded before questions were asked about pregnancy status.
The original database included information from 42,132 patients who received 106,641 units of red blood cells (76% from male donors, 12% from ever-pregnant donors, 12% from never-pregnant female donors). From this group, the researchers further assessed a “no-donor-mixture” cohort of 31,118 patients who received 59,320 units of red blood cells exclusively from male donors, exclusively from female donors without a history of pregnancy (never-pregnant donors), or exclusively from female donors with a history of pregnancy (ever-pregnant donors).
The investigation followed the recipients for a median of 245 days. The median age of the recipients was 65 years, and 16,123 (52%) were female. During follow-up, 3969 recipients died.
The hazard ratio (HR) for death after receiving one additional unit of red blood cells from a never-pregnant female donor, compared with receiving a unit from a male donor, was 0.93 (95% confidence interval [CI], 0.81 – 1.06) for male recipients and 1.01 (95% CI, 0.88 – 1.15) for female recipients. In contrast, the HR for death after one additional unit of red blood cells from an ever-pregnant female donor, compared with a unit from a male donor, was 1.13 (95% CI, 1.01 – 1.26) for male recipients and 0.99 (95% CI, 0.87 – 1.13) for female recipients.
The largest increase in mortality was found in male patients younger than 50 years who received transfusions from ever-pregnant donors (for ages 0 to 18 years: HR, 1.63; 95% CI, 1.02 – 2.61; for ages 18 to 50 years: HR, 1.50; 95% CI, 0.98 – 2.30).
Analysis of a subgroup who underwent single transfusions revealed 3-year cumulative mortality among male recipients of 13.5% after receiving a transfusion from a male donor and 13.1% after receiving a transfusion from a never-pregnant female donor (difference, 0.4%; 95% CI, −3.8% to 3.0%). The 3-year cumulative mortality among male recipients was 16.9% after receiving a transfusion from an ever-pregnant female donor (difference, 3.5%; 95% CI, −0.3% to 7.2%).
Among female recipients, mortality was 12.6% after a transfusion from a male donor and 12.0% after a transfusion from a never-pregnant female donor (difference, 0.6%; 95% CI, −3.7% to 2.6%) and 15.9% after a transfusion from an ever-pregnant female donor (difference, 3.3%; 95% CI, −0.5% to 7.1%).
For the full cohort (including individuals who had received blood from more than one of the three groups), HR of transfusion from an ever-pregnant female donor compared with a male donor was 1.08 (95% CI, 1.02 – 1.15) for all male recipients, 1.18 (95% CI, 0.82 – 1.69) for male recipients through age 17, and 1.43 (95% CI, 1.13 – 1.82) for male recipients aged 18 through 50. For female recipients, the HR for death after one additional unit of red blood cells from an ever-pregnant female donor compared to a male donor was 0.99 (95% CI, 0.93 – 1.07).
The researchers conclude, “Male recipients who received a transfusion from an ever-pregnant female donor had a statistically significant increase in mortality compared with those who received a transfusion from a male donor or from a female donor without a history of pregnancy. There was no significant association between pregnancy status of female donors of red blood cells and mortality among female recipients of red blood cell transfusions.”
An alternative hypothesis to an immune response against male antigens is iron-deficiency anemia in blood from females, which would possibly mean greater need for additional transfusions for recipients, but would not explain the sex difference for mortality among recipients.
Limitations of the study include the lack of information on cause of death and the absence of pregnancy information for earlier blood donations.
In an accompanying editorial, Ritchard G. Cable, MD, of the American Red Cross Blood Services in Farmington, Connecticut, and Gustaf Edgren, MD, PhD, of the Department of Medical Epidemiology and Biostatistics at the Karolinska Institute, Stockholm, Sweden, point out the complexity of the data and possible sources of confusion.
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Exclusion of patients who received transfusions from more than one of the three types of donors (male, ever-pregnant, and never-pregnant) could have excluded sicker patients who required more transfusions.
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The fact that blood from females has about 8% less hemoglobin may have influenced the number of transfusions that individuals required.
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Some of the older women in the overall cohort, who joined before pregnancy status was queried, may have been pregnant. Without this information, the study design could not capture waning effects of immunity with time.
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The greater effect among men younger than 50 could reflect the effect of androgens, not restriction to males.
Dr Cable and Dr Edgren suggest that if the immune response to paternal (Y chromosome-encoded) antigens is the underlying mechanism, then blood from mothers of sons should present a greater risk than blood from mothers of daughters. However, this was not examined in the current study.
“In light of the limitations of the study by Caram-Deelder et al, current criteria for blood donor selection should not change. However, additional investigation is needed,” Dr Cable and Dr Edgren write. They also advocate extending analysis to a more genetically diverse population than persons living in the Netherlands.
If the association between ever-pregnant female blood donors and increased male recipient mortality persists with expanded studies, then blood centers might institute sex-matched transfusions and improve methods of purifying red blood cell products, the editorial writers suggest.
Dr Zwaginga has received a speaking fee from Vifor Pharma and serves on the advisory councils of Novartis and Amgen Science. The other authors and the editorialist have disclosed no relevant financial relationships.
JAMA. Published online October 17, 2017. Abstract, Editorial
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