Borderline Anemia Linked to Higher Mortality Risk

Borderline anemia was associated with a higher risk of mortality in a prospective cohort study, according to researchers.

Among adults with borderline anemia — hemoglobin levels 0 to 1 g/dL above the WHO threshold for anemia — the 10-year standardized cumulative incidence of all-cause mortality was 18% higher compared with a reference group, reported Pierpaolo Pellicori, MD, of the University of Glasgow, and colleagues in Annals of Internal Medicine.

The WHO threshold for anemia is below 13 g/dL for men and below 12 g/dL for women, and the researchers said the study builds on the growing body of literature showing a U-shaped relationship between hemoglobin concentrations and mortality.

In comparison to the 10-year standardized cumulative incidence of 4.5% in the reference group — those with hemoglobin concentrations >1 to 3 g/dL above the WHO anemia threshold — mortality was higher in all other groups:

• >2 g/dL below: 12.5% (adjusted hazard ratio [aHR] 2.87, 95% CI 2.54-3.25)
• >1 to 2 g/dL below: 11.2% (aHR 2.53, 95% CI 2.33-2.75)
• >0 to 1 g/dL below: 7.9% (aHR 1.74, 95% CI 1.67-1.82)
• 0 to 1 g/dL above: 5.3% (aHR 1.18, 95% CI 1.15-1.21)
• >3 to 4 g/dL above: 4.7% (aHR 1.05, 95% 1.02-1.09)
• >4 g/dL above: 5.7% (aHR 1.31, 95% CI 1.21-1.41)

Both high and low hemoglobin levels are associated with negative health outcomes in older adults, including cognitive decline, CVD, and increased risks of hospitalization and death. While high hemoglobin (polycythemia) is very rare, low hemoglobin (anemia) is very common.

“Hemoglobin concentration values should be assessed in clinical context, including symptoms, repeated measurements of hemoglobin concentration, red blood cell indices, evidence of iron deficiency, and other potential underlying causes,” Pellicori and team concluded. “However, our observations suggest that values up to 1 g/dL above the current WHO definition for anemia (borderline anemia) may warrant investigation rather than automatic reassurance, particularly in people with a high prevalence of iron deficiency, such as older adults and those with CVD [cardiovascular disease].”

In a press release, Pellicori noted that “the current WHO thresholds have served clinical practice for decades, but our findings suggest that the relationship between hemoglobin concentration and long-term health is more nuanced than a single diagnostic cut-off can capture. Whether this should influence clinical practice is an important question for future research.”

The authors also evaluated the associations between hemoglobin concentrations and cardiovascular- and cancer-related mortality, finding that the risk for both was consistently elevated among people meeting the WHO definition of anemia, as well as among those with borderline anemia.

Participants with hemoglobin concentrations more than 3 to 4 g/dL and more than 4 g/dL above the WHO definition also had a greater risk for CVD-related death, but the risk for cancer mortality was largely attenuated, the authors noted.

The study cohort included 502,188 adults across 22 centers in the U.K. Biobank who were recruited from 2006 to 2010. Median age was 58 years, and 54.4% were women. Median follow-up was 13.6 years.

Most participants had hemoglobin concentrations 1 to 3 g/dL above the WHO anemia threshold (64.9%), while 4.4% were below the threshold, and 1% had polycythemia.

Women, particularly younger women, were more likely than men to have lower hemoglobin concentrations. Median concentrations were 13.4 g/dL in women younger than 60, 13.6 g/dL in women 60 and older, 15.1 g/dL in men younger than 60, and 14.9 g/dL in men 60 and older.

When stratifying results by age and sex, borderline anemia was associated with higher risks for all-cause, cardiovascular, and cancer mortality in men of all ages and in women 60 and older, “and this pattern persisted after adjusting for a broad range of [cardiovascular] risk factors and comorbidities,” the authors wrote.

Pellicori and colleagues acknowledged that their study had several limitations. Hemoglobin concentrations were measured once at baseline, which may not capture changes over time, they noted. In addition, participants in the U.K. Biobank are predominantly in middle age or older, healthier, less deprived, and mostly white, “so findings may not generalize to younger, more vulnerable, older, or more ethnically diverse populations,” they wrote.