Borderline-low hemoglobin levels linked to increased mortality

1. In this prospective cohort study, mortality risk was higher among participants with hemoglobin concentrations below, 0 to 1 g/dL above, or more than 3 g/dL above the World Health Organization (WHO) anemia threshold.

2. Cardiovascular (CV) and cancer mortality were consistently higher among participants meeting the WHO definition of anemia and those with hemoglobin concentrations 0 to 1 g/dL above the threshold.

Evidence Rating Level: 2 (Good)

Study Rundown: An estimated 1.6 billion people worldwide have anemia, with iron deficiency being the most common cause. Although the World Health Organization (WHO) definition of anemia is widely used in clinical practice, it is based on cross-sectional studies conducted more than 50 years ago in young adults of predominantly White European and North American ancestry, potentially limiting its applicability to contemporary, diverse populations. This study assessed the association between hemoglobin concentration and subsequent mortality in a general population from the UK Biobank. Crude all-cause, cardiovascular (CV), and cancer mortality demonstrated U-shaped associations with hemoglobin concentration, with higher mortality among participants with levels more than 2 g/dL below or 4 g/dL above the WHO anemia threshold. Participants with hemoglobin concentrations 0 to 1 g/dL above the threshold also had slightly higher mortality, whereas mortality was lowest at concentrations 1 to 3 g/dL above the threshold. CV and cancer mortality were consistently elevated among participants meeting the WHO definition of anemia and those with hemoglobin concentrations 0 to 1 g/dL above the threshold. Concentrations more than 3 g/dL above the threshold were also associated with increased CV mortality but attenuated cancer mortality. Limitations included reliance on a single baseline hemoglobin measurement and a predominantly White study population. Nevertheless, these findings suggest that hemoglobin concentrations slightly above current WHO anemia thresholds may still be associated with increased mortality and warrant further clinical investigation rather than automatic reassurance.

Click to read this study in AIM

Relevant Reading: Haemoglobin thresholds to define anaemia from age 6 months to 65 years: estimates from international data sources

In-Depth [prospective cohort]: This prospective cohort study assessed the association between hemoglobin concentration and subsequent mortality in a contemporary British population. Data were obtained from 502,188 UK Biobank participants aged 37 to 73 years who were recruited between 2006 and 2010. Participants were classified into seven groups according to hemoglobin concentration relative to sex-specific WHO anemia thresholds (<13.0 g/dL for men and <12.0 g/dL for women). The primary outcome was all-cause mortality over the entire follow-up and at 1, 3, 5, and 10 years; secondary outcomes included CV and cancer mortality. Median age was 58 years, and 45.6% of participants were men. Most participants (64.9%) had hemoglobin concentrations 1 to 3 g/dL above the WHO threshold, whereas 4.4% met the WHO definition of anemia. Over a median follow-up of 13.6 years, 43,764 deaths occurred. Crude all-cause, CV, and cancer mortality demonstrated U-shaped associations with hemoglobin concentration. Mortality was highest among participants with concentrations more than 2 g/dL below the WHO threshold and was also elevated at concentrations more than 4 g/dL above the threshold. The lowest mortality was observed at concentrations 1 to 3 g/dL above the threshold. At 10 years, standardized cumulative all-cause mortality was 4.5% (95% confidence interval [CI], 4.4%-4.5%) in this reference group compared with 12.5% (95% CI, 11.2%-14.0%) among participants more than 2 g/dL below the threshold, corresponding to an absolute risk difference of 8.1 percentage points. Notably, participants only 0 to 1 g/dL above the threshold also had higher mortality (5.3%; absolute risk difference, 0.8 percentage points). CV and cancer mortality were consistently elevated among participants meeting WHO anemia criteria and those 0 to 1 g/dL above the threshold. Concentrations more than 3 g/dL above the threshold were associated with increased CV mortality but attenuated cancer mortality. U-shaped associations were observed across age groups in men and among women aged 60 years or older but were less consistent in younger women. Sensitivity analyses excluding early deaths and subdividing the reference range yielded similar findings. Overall, hemoglobin concentrations 1 to 3 g/dL above current WHO anemia thresholds were associated with the lowest mortality risk.

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