All-cause mortality rates were lowest in adults with hemoglobin concentrations slightly higher than the World Health Organization (WHO) threshold for anemia, based on data from a cohort study of more than 500,000 individuals.

The WHO anemia thresholds of a hemoglobin concentration < 13 g/dL in men and < 12 g/dL in women have remained largely unchanged for more than 50 years, said lead author Malek Ahmad, MBBS, a PhD student at the University of Glasgow, Glasgow, Scotland.

“We know that anemia is associated with a worse prognosis in patients with heart disease, but its significance in the general population is less clear,” said Ahmad.

In a study published in the Annals of Internal Medicine, the researchers reviewed data from the UK Biobank, which includes a prospective cohort of 502,188 adults aged 37-73 years enrolled at one of 22 assessment centers in the UK between 2006 and 2010. The median age of the participants was 58 years, and 54.4% were women. The primary outcome was all-cause mortality at follow-up points of 1, 3, 5, and 10 years, and overall. The median follow-up was 13.6 years.

A total of 43,764 individuals died during the study period. Overall, all-cause mortality, cardiovascular mortality, and cancer mortality showed U-shaped patterns of association with hemoglobin levels. The highest mortality rates were in those with hemoglobin levels > 2 g/dL below the WHO anemia threshold, and also in individuals with levels > 4 g/dL above the threshold. The lowest mortality rates occurred in the reference group of individuals with hemoglobin levels of 1-3 g/dL above the WHO threshold.

In an adjusted model, the 10-year standardized cumulative mortality rate was 4.5% in the reference group compared to 12.5% in those with hemoglobin levels > 2 g/dL below the threshold and 5.3% in those with levels from 0 to 1 g/dL above the threshold. 

In further analysis, risk for both cancer-related and cardiovascular-related mortality was elevated in individuals who met the WHO criteria for anemia and those with borderline anemia (hemoglobin, 0-1 g/dL above the threshold).

“Importantly, however, risk began to increase even before hemoglobin fell below the WHO threshold. People whose hemoglobin was approximately 1-3 g/dL above the threshold had the most favourable prognosis,” Ahmad said.

The findings were limited by several factors, including the measurement of hemoglobin at baseline and the relatively homogenous study population, the authors noted. Other limitations included the inability to distinguish anemia attributable to low hemoglobin from other causes including iron deficiency, chronic inflammation, or occult disease, they said.

Takeaways and Next Steps

The findings reflect similar patterns observed in populations from other areas including Greater Glasgow and Clyde, Scotland, and in outpatients with heart failure in the UK, said corresponding author Pierpaolo Pellicori, MD, a clinical cardiologist and senior lecturer at the University of Glasgow.

“What continues to surprise me is how common anemia is in clinical practice and how often it is overlooked,” he noted. “Our findings suggest that a hemoglobin concentration at the lower end of the normal range should not necessarily be considered reassuring, particularly when there are other reasons to be concerned about a person’s health,” he said.

The new study suggests the need for attention to concentrations near the lower end of the normal range and to consider whether further assessment is needed, particularly to identify reversible causes of anemia, said senior author John G.F. Cleland, MD, also of the University of Glasgow.

Iron deficiency can be substantial before hemoglobin falls below the WHO threshold for anemia, and previous research suggests that iron deficiency is common in people within the borderline range, said Cleland. “If future studies show that investigating borderline hemoglobin concentrations identifies important underlying disease, or that correcting iron deficiency improves symptoms, quality of life, or clinical outcomes, there would be a strong argument for reconsidering the current definition of anemia,” he said.

The current study represents a starting point, Pellicori emphasized. “We now need to understand why people with borderline hemoglobin concentrations have a poorer prognosis,” he said. “We also need prospective studies to determine whether identifying and correcting iron deficiency, or treating other reversible causes of anemia, improves well-being and clinical outcomes,” Pellicori added.

Too Soon to Change Clinical Practice

The WHO thresholds, established in 1959, were based on a smaller and largely younger population, said William Callahan, DO, a family medicine physician at Jefferson Health in Abington, Pennsylvania, who was not involved in the study.

The current study, with more than 500,000 participants and a follow-up of up to 14 years, is important for insight into the original data from 1959, and the potential need for further research, said Callahan.

The study suggests that all-cause mortality was lowest in individuals with a hemoglobin ranging from 1-3 g/dL above the traditional WHO threshold, Callahan said. However, the results do not suggest that clinicians should suddenly work up patients outside of this range, he added. “Instead, the study raises important questions, including what is driving higher mortality in borderline ranges, and why, as the study suggests, does it impact older adults and men more so than young women,” he noted. Randomized trials are needed to specifically clarify any benefits of intervention in patients who fall at or just below the normal range, said Callahan. “Until more studies are done, clinical practice should largely remain unchanged,” he said.

The study received no outside funding. Disclosure information for the authors is available in the original study publication. Callahan had no financial conflicts to disclose.