Highlights
• In an international prospective cohort (ALICE), 31.7% of patients undergoing major surgery had preoperative anaemia.
• Among patients with a confirmed aetiology, iron deficiency was the most frequent cause (55.2%), but vitamin B12 deficiency (7.7%) and folate deficiency (14.5%) were also common.
• Multiple concurrent causes were frequent, and iron deficiency predominated across sexes, ages, and countries.
Background: Why preoperative anaemia matters
Anaemia before major surgery is a robust, independent predictor of perioperative morbidity, increased transfusion, prolonged hospital stay, and worse short- and long-term outcomes. Patient Blood Management (PBM) frameworks emphasize identifying and treating anaemia before elective operations to reduce transfusion-related risks and optimize recovery. Historically, iron deficiency has been assumed to be the dominant underlying cause in surgical populations and has rightly shaped much of preoperative screening and treatment strategies. However, anaemia is frequently multifactorial — arising from nutrient deficiencies (iron, vitamin B12, folate), chronic kidney disease, inflammation, bone marrow disorders, or combined mechanisms — and effective management depends on correct aetiological diagnosis.
Study design: The ALICE international cohort
ALICE (Aetiology and prevalence of preoperative anaemia in patients undergoing major surgery) is a prospective, multicentre, observational cohort conducted across 79 hospitals in 20 countries (five continents). The study enrolled adults (≥18 years) undergoing major surgery with an expected postoperative in‑hospital stay ≥24 hours; autologous blood donors were excluded. Data were extracted from hospital records and preoperative assessments. The primary outcomes were prevalence of preoperative anaemia (hemoglobin <120 g/L for women and <130 g/L for men) and the distribution of confirmed aetiologies among anaemic patients. Aetiologies could overlap; the analysis of causes was restricted to anaemic patients for whom at least one cause could be confirmed per the study protocol and local laboratory testing.
Key findings
The study recruited 2,830 patients between Aug 26, 2019, and Dec 26, 2021; 2,702 were included in the analysis (1,417 men, 1,279 women, and six with gender dysphoria). Main findings:
- Prevalence: 856 of 2,702 patients (31.7%; 95% CI 31.2–32.2) had preoperative anaemia by the study hemoglobin thresholds.
- Aetiology (in 782 anaemic patients with at least one confirmed cause):
- Iron deficiency: 432 patients (55.2%; 95% CI 48.9–61.6).
- Vitamin B12 deficiency: 60 patients (7.7%; 95% CI 6.6–8.7).
- Folate deficiency: 113 patients (14.5%; 95% CI 12.2–16.7).
- Chronic kidney disease (CKD)-related anaemia: 68 patients (8.7%; 95% CI 8.1–9.3).
- Other causes (including haemolysis, bone marrow disease, unexplained anaemia): 48 patients (6.1%; 95% CI 4.5–7.8).
Patients could be assigned to more than one aetiology. Importantly, iron deficiency was the most common cause across sexes, age groups, and countries.
Clinical interpretation and implications
ALICE confirms that preoperative anaemia remains common in contemporary surgical practice worldwide and that iron deficiency is the single most frequent identifiable cause. Several clinical implications flow from these observations:
1) Broaden the diagnostic perspective beyond iron alone
Although iron deficiency predominates, a non-negligible fraction of anaemic patients had vitamin B12 or folate deficiency. These nutrient deficits are clinically relevant because they require different therapies (parenteral or oral B12; oral folic acid) and, if unrecognized, may respond poorly to iron repletion alone. Clinicians should therefore consider a targeted panel to identify common, correctable causes: hemoglobin, ferritin and/or transferrin saturation (for iron status), vitamin B12, red cell folate (or serum folate), renal function (eGFR), and markers of inflammation if available. The timing of testing should allow therapeutic intervention when surgery is elective.
2) Individualized treatment pathways
When iron deficiency is confirmed, treatment choice (oral vs intravenous iron) should be individualized. Intravenous iron may be preferred when rapid hemoglobin recovery is required or when oral iron is not tolerated. However, randomized trials have delivered mixed results on whether preoperative IV iron reduces transfusion or short-term clinical endpoints; therefore, PBM programmes should align treatment choices with available evidence, logistics, and patient factors. For vitamin B12 and folate deficiencies, replacement therapy is straightforward and inexpensive and should be instituted promptly.
3) Expect multiple concurrent causes
Because patients frequently have more than one contributing factor, a single corrective strategy (e.g., iron alone) may be insufficient. Comprehensive investigation and combined treatment (iron plus B12/folate replacement; address CKD; manage chronic inflammation) increase the chance of meaningful hemoglobin response before surgery.
4) Implementation and timing matter
To enable effective correction, screening must occur early in the preoperative pathway — ideally several weeks before planned surgery. Health systems need workflows that ensure lab testing, timely result review, and prompt initiation of therapy. Integration into existing preoperative assessment clinics and alignment with PBM programmes will optimize uptake.
Expert commentary: strengths, limitations, and external evidence
ALICE’s strengths include its prospective design, large sample size, international scope, and focus on confirmed aetiologies rather than assumptions. The consistent predominance of iron deficiency across diverse settings strengthens external validity.
Limitations are inherent to observational cohorts: heterogeneity of laboratory testing methods and definitions across centres, potential missingness of confirmatory tests (aetiology analysis excluded some anaemic patients lacking confirmation), and lack of longitudinal outcome data linking specific aetiologies or targeted treatments to perioperative morbidity. The study does not evaluate whether correcting the identified deficiencies changed clinical outcomes — this requires randomized trials or implementation studies.
Contextualizing with trial evidence, interventional studies of preoperative IV iron have had variable results. Some trials demonstrate improved hemoglobin recovery but not consistent reductions in transfusion or short-term morbidity. This nuanced evidence underscores the need for targeted, timely correction of confirmed deficiencies rather than blanket preoperative iron therapy for all anaemic patients.
Practical takeaways for clinicians
- Adopt routine preoperative screening for anaemia for all patients scheduled for major surgery, using sex-specific hemoglobin thresholds.
- When anaemia is identified, obtain a focused diagnostic panel: ferritin and transferrin saturation (or ferritin with CRP interpretation), vitamin B12, folate, and renal function. Interpret ferritin cautiously if inflammation is present.
- Treat confirmed iron deficiency with oral or IV iron based on urgency, tolerance, and logistics; treat vitamin B12 and folate deficiencies with appropriate supplementation.
- Do not assume iron deficiency is the only cause — assess for CKD, inflammation, haemolysis, or bone marrow disorders when indicated.
- Establish preoperative anaemia pathways within PBM programmes to ensure testing, treatment, and follow-up are systematic and timely.
Research and policy priorities
ALICE highlights several areas for further work:
- Randomized trials that assess outcome benefits from early, aetiology-targeted correction (including combined nutrient repletion) vs usual care.
- Implementation research to define cost-effective screening panels and optimal timing for testing and therapies in diverse health systems.
- Studies to refine diagnostic thresholds and biomarkers in the context of inflammation and multimorbidity.
- Evaluation of integrated PBM programmes that combine screening, diagnostics, and tailored therapies on transfusion rates, perioperative complications, length of stay, and patient-centered outcomes.
Conclusion
The ALICE study provides robust, international evidence that preoperative anaemia is common in patients undergoing major surgery and that iron deficiency is the predominant confirmed cause. Nonetheless, vitamin B12 and folate deficiencies are clinically significant contributors and must not be overlooked. Clinical pathways should broaden diagnostic testing beyond iron alone, ensure early identification, and offer targeted treatment. Embedding these steps within PBM programmes promises to improve perioperative care and patient outcomes, but high-quality trials and implementation studies are needed to define the most effective strategies.
Funding and trial registration
Funding: None declared by the study authors. ClinicalTrials.gov registration: NCT03978260.
References
1. Choorapoikayil S, Baron DM, Spahn DR, et al.; ALICE study collaborators. The aetiology and prevalence of preoperative anaemia in patients undergoing major surgery (ALICE): an international, prospective, observational cohort study. Lancet Glob Health. 2025 Dec;13(12):e2041-e2050. doi:10.1016/S2214-109X(25)00320-1. PMID: 41240945.
2. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. WHO; 2011. (WHO/NMH/NHD/MNM/11.1)
3. National Blood Authority (Australia). Patient Blood Management Guidelines: Module 2 — Perioperative. 2012 (updated resources available at www.blood.gov.au).
