Significant association between anemia and higher risk for COVID-19 mortality: A meta-analysis of adjusted effect estimates

a b s t r a c t

Objective: This study aimed to evaluate whether there was a significant relationship between anemia and the risk for mortality among coronavirus disease 2019 (COVID-19) patients by a quantitative meta-analysis based on the adjusted effect estimates.

Methods: A systematic search was conducted in electronic databases to identify all published literature. A random-effects meta-analysis model was used to estimate the Pooled effect size and 95% confidence interval (CI). Heterogeneity test, Begg’s test, subgroup analysis and meta-regression were performed.

Results: Twenty-three articles with 573,928 COVID-19 patients were included in the quantitative meta-analysis. There was a significant association between anemia and an elevated risk of COVID-19 mortality (pooled effect size = 1.47, 95% CI [1.30-1.67]). We observed this significant association in the further subgroup analyses by age, proportion of males, sample size, study design, region and setting. Sensitivity analysis exhibited that our re- sults were reliable. Begg’s test showed that there was no publication bias. Meta-regression indicated that the tested variables might not be the source of heterogeneity.

Conclusion: Our meta-analysis based on risk factors-adjusted effect estimates indicated that anemia was indepen- dently associated with a significantly elevated risk for mortality among COVID-19 patients.

(C) 2022

  1. Introduction

Recently, Taneri et al. have performed a systematic review and meta- analysis to explore the prognostic value of biomarkers of anemia among patients with coronavirus diseases 2019 (COVID-19) [1]. They found non-significant difference in Hemoglobin levels between survivors and non-survivors among COVID-19 patients, indicating that anemia might not be a risk predictor for COVID-19 mortality. This is an extremely inter- esting study, but the pooled effect size was estimated on the basis of un-adjusted effect in Taneri et al’ study [1], which suggests that some confounding factors were not taken into account when the authors eval- uated the association between anemia and COVID-19 mortality. To the best of our knowledge, a few variables such as age, sex and pre- existing chronic health conditions (hypertension, diabetes mellitus, car- diovascular disease and Chronic liver disease, etc.) have been identified to influence the clinical outcomes of COVID-19 patients [2-8], which

* Corresponding author at.: Department of Epidemiology, School of Public Health, Zhengzhou University, No. 100 of Science Avenue, Zhengzhou, 450001, China.

E-mail address: [email protected] (H. Yang).

might confound the association between anemia and the risk for COVID-19 mortality. We therefore performed a meta-analysis based on the risk factors-adjusted effect estimates to investigate whether there was a significant association between anemia and higher risk for mortal- ity from COVID-19.

  1. Methods

We carried out a systematic search in the electronic databases of Web of Science, PubMed, Springer Link, Elsevier Sciencedirect, EMBASE, Cochrane Library and Scopus to identify all potential articles published on March 13, 2022. The keywords were utilized as follows: (“coronavirus disease 2019” or “COVID-19” or “severe acute respiratory syndrome coronavirus-2″ or “SARS-CoV-2” or “2019 novel coronavirus” or “2019-nCoV”) and (“non-survivor” or “deceased” or “death” or “fatal- ity” or “mortality”) and (“anemia” or “hemoglobin”). Eligible studies in English were included when they were peer-reviewed and presented the risk factors-adjusted effect estimates on the association between anemia and COVID-19 mortality. Preprints, review papers, comments, case reports, errata and studies presenting un-adjusted effect estimates


0735-6757/(C) 2022

Image of Fig. 1

Fig. 1. Flow chart of the process of study selection.

on the association between anemia and COVID-19 mortality were ex- cluded accordingly. Additional articles were eligibly included through looking into the reference lists of the included studies and relevant reviews. The detailed extraction of the each included article was

completed independently by two authors using a standardized form. Discrepancies were arbitrated by a third author. The following informa- tion extracted from the eligible literature, including name of the first au- thor, number of COVID-19 patients, the proportion of males, age (mean

Table 1

General information of the eligible studies included in this meta-analysis





Male (%)

Study design

Adjusted effect (95% CI)


Kim DH





Retrospective study

2.08 (1.40-3.11)

All patients

Pilgram L

Lean European Open Survey




Retrospective study

3.21 (1.17-8.82)

All patients




65 +- 16


Retrospective study

1.523 (1.008-2.303)

Hospitalized patients

Tremblay D



59 (42-71)


Prospective study

1.26 (1.06-1.51)

All patients

Bellmann-Weiler R



68 (53-80)


Retrospective study

5.063 (1.260-20.345)

Hospitalized patients

Khosravi B



60 +- 16


Retrospective study

3.86 (1.52-9.77)

Hospitalized patients

Tang O



71.2 +- 51.7


Prospective study

1.12 (0.80-1.57)

All patients

Turgutalp K



63 (53-71)


Retrospective study

0.541 (0.284-1.029)

Hospitalized patients

Le Borgne P



63.1 (50.0-73.0)


Retrospective study

5.14 (1.19-22.19)

Hospitalized patients

Lee J





Retrospective study

1.74 (1.10-2.77)

All patients

Faghih Dinevari M



64.43 +- 17.16


Prospective study

1.68 (1.10-2.57)

Hospitalized patients

Giacomelli A



61 (52-70)


Prospective study

2.13 (1.21-3.76)

Hospitalized patients

Meisel E



63.6 +- 16.8


Retrospective study

1.50 (0.83-2.71)

Hospitalized patients

Kompaniyets L



66 (53-77)


Retrospective study

1.17 (1.14-1.19)

Hospitalized patients

Hermel DJ



61.23 +- 16.70


Retrospective study

1.74 (1.07-2.85)

Hospitalized patients

Bushman D



56 (23-64)


Case-control study

1.69 (1.01-2.80)

Hospitalized patients

Pagano L



65 (54-74)


Retrospective study

2.022 (0.724-5.645)

All patients

Chojnicki M



77.5 +- 10.0


Prospective study

2.21 (1.33-3.68)

Hospitalized patients

Bernardo J



68.9 +- 17.9


Retrospective study

0.972 (0.899-1.051)

Hospitalized patients

Alhasan KA

Saudi Arabia


52.8 +- 16.6


Retrospective study

2.31 (0.63-8.48)

Hospitalized patients

Kim YJ





Retrospective study

1.917 (1.134-2.441)

All patients

Buso G

International RIETE registry




Retrospective study

1.14 (0.77-1.69)

All patients

AbuRuz S

United Arab Emirates


44.3 +- 13.4


Retrospective study

1.76 (1.03-3.00)

Hospitalized patients

Note: # the age (years) was presented as mean +- standard deviation or median (interquartile range, IQR); CI, confidence interval; NR, not clearly reported; RIETE, Registro Informatizado de Enfermedad TromboEmbolica; USA, the United states of America.

+- standard deviation (SD) or median (interquartile range)), study de- sign, country or region, the number and percent of COVID-19 patients with anemia, adjusted effect size (95% confidence interval (CI)), death outcome and setting. This systematic meta-analysis was performed in accordance with the guidelines of the Preferred Reporting Items for Sys- tematic Reviews and Meta-Analyses (PRISMA) checklist (Table S1) [9]. All statistical analyses were carried out by using R software with the “meta” package. Heterogeneity across studies was measured by I2 statis- tic and standard Cochran’s Q analysis. The pooled effect size with its 95% CI was calculated to measure the association between anemia and the risk for COVID-19 mortality by a random-effects meta-analysis model. The stability of the overall results was examined by the leave-one-out sensitivity analysis. Potential publication bias was evaluated by Begg’s rank correlation analysis. Meta-regression and subgroup analyses were also conducted. Statistically significant difference was defined as

P < 0.05.

  1. Results

Fig. 1 showed the flow chart of related literature search and Selection process. A total of twenty-three articles with 573,928 COVID-19 patients were eligibly included in this quantitative meta-analysis [10-32]. The characteristics of the eligible studies are summarized in Table 1.

The pooled effect size with 95% CI on the basis of risk factors- adjusted effect estimates is presented in Fig. 2A. We observed that there was a significant association between anemia and higher risk for COVID-19 mortality (pooled effect size = 1.47, 95% CI [1.30-1.67]). We also observed this significant association in the further subgroup analyses stratified by sample size (pooled effect size = 1.54, 95% CI [1.29-1.84] for >=1000 cases and pooled effect size = 1.58, 95% CI [1.21-2.06] for <1000 cases), proportion of male patients (pooled effect size = 1.38, 95% CI [1.20-1.58] for >=50% and pooled effect size = 1.72, 95% CI [1.32-2.25] for <50%), age (pooled effect size = 1.42, 95% CI [1.23-1.65] for age >= 60 years old and pooled effect size = 1.43, 95% CI [1.23-1.66] for age < 60 years old), region (pooled effect size = 1.17, 95% CI [1.15-1.20] for North America; pooled effect size = 1.68,

95% CI [1.29-2.19] for Asia and pooled effect size = 2.21, 95% CI [1.27-3.86] for Europe), study design (pooled effect size = 1.46, 95% CI [1.26-1.70] for retrospective studies and pooled effect size = 1.50, 95% CI [1.17-1.91] for prospective studies) and setting (pooled effect size = 1.45, 95% CI [1.24-1.70] for hospitalized patients and pooled ef- fect size = 1.52, 95% CI [1.23-1.86] for all patients). The sensitivity anal- ysis demonstrated that our results were reliable and robust (Fig. 2B). There was no potential publication bias detected in Begg’s test (P = 0.196, Fig. 2C). Meta-regression suggested that the tested variables in- cluding sample size (P = 0.720), proportion of males (P = 0.121), age (P = 0.628), study design (P = 0.907), region (P = 0.360) and setting (P = 0.783) might not be the source of heterogeneity.

  1. Discussion

Although the published literature has investigated the relationship between anemia and the risk for mortality among COVID-19 patients, their conclusions were inconsistent [15,17]. Our data based on risk factors-adjusted effect estimates showed that anemia was associated with a significantly elevated risk of COVID-19 mortality, which suggests that anemia might be an independent risk predictor for the fatal out- come of COVID-19 patients. Further subgroup analyses stratified by sample size, age, proportion of males, region, study design and setting also supported the overall results. COVID-19 patients had respiratory system damages and increased oxygen demand, and bore lower hemo- globin levels, and this situation further reduces the oxygen supply to the peripheral tissues, as the disease progresses, persistent hypoxic condi- tion may lead to peripheral tissue ischemia or multiple organ failure [12]. This may explain the higher mortality among COVID-19 patients with anemia in comparison to those without anemia.

Image of Fig. 2

Fig. 2. The forest plots indicated that there was a significant association between anemia and an elevated risk for mortality among patients with coronavirus disease 2019 (COVID-19) on the basis of twenty-three studies with 573,928 cases (A); Leave-one-out sensitivity analysis demonstrated the stability of the overall results (B); Begg’s test re- vealed that there was no obvious publication bias (C).

This current meta-analysis still has several limitations. Firstly, most of the included studies were retrospective. Thus, further meta- analyses based on prospective studies with large sample sizes are re- quired to verify our findings. Secondly, the pooled effect sizes were cal- culated on the basis of adjusted effect estimates, but the risk factors adjusted in the included studies were not completely consistent. Thirdly, the definition of anemia (the level of hemoglobin) in the in- cluded literature was not fully consistent. Finally, the heterogeneity could not be ignored. Although we conducted meta-regression to ex- plore the source of heterogeneity, no source of heterogeneity was found.

In conclusion, our meta-analysis based on risk factors-adjusted effect estimates showed that anemia was independently associated with a sig- nificantly higher risk for mortality among patients with COVID-19. Fur- ther well-designed studies with more eligible literature and large sample sizes are warranted to verify our current findings.


This study was supported by grants from Henan Young and Middle- aged Health Science and Technology Innovation Talent Project (No. YXKC2021005) and National Natural Science Foundation of China (No. 81973105). The funders have no role in the data collection, data analy- sis, preparation of manuscript and decision to submission.

Author contributions

Haiyan Yang and Yadong Wang conceptualized the study. Lan Nan, Ruiying Zhang, Yuqing Hao and Ying Wang performed literature search and data extraction. Mengke Hu, Lan Nan, Ying Wang and Yuqing Hao analyzed the data. Ying Wang and Ruiying Zhang wrote the manuscript. All the authors approved the final manuscript.

Data availability statement

The data that support the findings of this study are included in this article and available from the corresponding author upon reasonable re- quest.

CRediT authorship contribution statement

Lan Nan: Writing – review & editing, Methodology, Investigation, Formal analysis. Mengke Hu: Writing – review & editing, Methodology, Investigation, Formal analysis. Ruiying Zhang: Writing – review & editing, Methodology, Investigation. Yuqing Hao: Writing – review & editing, Methodology, Investigation. Yadong Wang: Writing – review & editing, Conceptualization. Haiyan Yang: Conceptualization.

Declaration of Competing Interest

All authors declare that they have no any potential conflict of inter- est.


We would like to thank Jie Xu, Hongjie Hou, Xueya Han, Shuwen Li, Jiahao Ren, Yang Li, Peihua Zhang, Jian Wu, Wenwei Xiao, Xuan Liang and Li Shi (All are from Department of Epidemiology, School of Public Health, Zhengzhou University) for their kind help in searching articles and collecting data, and valuable suggestions for analyzing data.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2022.06.030.


  1. Taneri PE, Gomez-Ochoa SA, Llanaj E, Raguindin PF, Rojas LZ, Roa-Diaz ZM, et al. Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis. Eur J Epidemiol. 2020;35(8):763-73.
  2. Mesas AE, Cavero-Redondo I, Alvarez-Bueno C, Sarria Cabrera MA, Maffei de Andrade S, Sequi-Dominguez I, et al. Predictors of in-hospital COVID-19 mortality: a comprehensive systematic review and meta-analysis exploring differences by age, sex and health conditions. PLoS One. 2020;15(11):e0241742.
  3. Liang X, Shi L, Wang Y, Xiao W, Duan G, Yang H, et al. The association of hyperten- sion with the severity and mortality of COVID-19 patients: evidence based on ad- justed effect estimates. J Inf Secur. 2020;81(3) e44-e7.
  4. Liang X, Xu J, Xiao W, Shi L, Yang H. The association of diabetes with COVID-19 dis- ease severity: evidence from adjusted effect estimates. Hormones. 2021;20(2): 409-14.
  5. Yang H, Xu J, Liang X, Shi L, Wang Y. Chronic liver disease independently associated with COVID-19 severity: evidence based on adjusted effect estimates. Hepatol Int. 2021;15(1):217-22.
  6. Zhang R, Hao Y, Wang Y, Yang H. Significant association between ischemic heart dis- ease and elevated risk for COVID-19 mortality: a meta-analysis. Am J Emerg Med. 2022;55:95-7.
  7. Yang H, Liang X, Xu J, Hou H, Wang Y. Meta-analysis of atrial fibrillation in patients with COVID-19. Am J Cardiol. 2021;144:152-6.
  8. Li S, Hu M, Zhang R, Xu J, Hou H, Wang Y, et al. The association between myocardial infarction and COVID-19 related mortality: a meta-analysis based on adjusted effect estimates. Am J Emerg Med. 2022;57:227-9.
  9. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg (London, England). 2010;8(5):336-41.
  10. Kim DH, Park HC, Cho A, Kim J, Yun KS, Kim J, et al. Age-adjusted Charlson comorbid- ity index score is the best predictor for severe clinical outcome in the hospitalized patients with COVID-19 infection. Medicine. 2021;100(18):e25900.
  11. Pilgram L, Eberwein L, Wille K, Koehler FC, Stecher M, Rieg S, et al. Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease. Infection. 2021;49(4):725-37.
  12. Oh SM, Skendelas JP, Macdonald E, Bergamini M, Goel S, Choi J, et al. On-admission anemia predicts mortality in COVID-19 patients: a single center, retrospective cohort study. Am J Emerg Med. 2021;48:140-7.
  13. Tremblay D, Rapp JL, Alpert N, Lieberman-Cribbin W, Mascarenhas J, Taioli E, et al. Mild anemia as a single independent predictor of mortality in patients with COVID-19. EJHaem. 2021. https://doi.org/10.1002/jha2.167. Epub ahead of print.
  14. Bellmann-Weiler R, Lanser L, Barket R, Rangger L, Schapfl A, Schaber M, et al. Prevalence and predictive value of Anemia and dysregulated Iron homeostasis in patients with COVID-19 infection. J Clin Med. 2020;9(8).
  15. Khosravi B, Aghaghazvini L, Sorouri M, Naybandi Atashi S, Abdollahi M, Mojtabavi H, et al. Predictive value of initial CT scan for various adverse outcomes in patients with COVID-19 pneumonia. Heart & Lung. 2021;50(1):13-20.
  16. Tang O, Bigelow BF, Sheikh F, Peters M, Zenilman JM, Bennett R, et al. Outcomes of nursing home COVID-19 patients by initial symptoms and comorbidity: results of universal testing of 1970 residents. J Am Med Dir Assoc. 2020;21(12) 1767-73.e1.
  17. Turgutalp K, Ozturk S, Arici M, Eren N, Gorgulu N, Islam M, et al. Determinants of mortality in a large group of hemodialysis patients hospitalized for COVID-19. BMC Nephrol. 2021;22(1):29.
  18. Le Borgne P, Solis M, Severac F, Merdji H, Ruch Y, Alame Intern K, et al. SARS-CoV-2 viral load in nasopharyngeal swabs in the emergency department does not predict COVID-19 severity and mortality. Acad Emerg Med. 2021;28(3):306-13.
  19. Lee J, Park SS, Kim TY, Lee DG, Kim DW. Lymphopenia as a biological predictor of outcomes in COVID-19 patients: a Nationwide cohort study. Cancers. 2021;13(3).
  20. Faghih Dinevari M, Somi MH, Sadeghi Majd E, Abbasalizad Farhangi M, Nikniaz Z. Anemia predicts poor outcomes of COVID-19 in hospitalized patients: a prospective study in Iran. BMC Infect Dis. 2021;21(1):170.
  21. Giacomelli A, De Falco T, Oreni L, Pedroli A, Ridolfo AL, Calabro E, et al. Impact of gen- der on patients hospitalized for SARS-COV-2 infection: a prospective observational study. J Med Virol. 2021;93(7):4597-602.
  22. Meisel E, Efros O, Bleier J, Beit Halevi T, Segal G, Rahav G, et al. folate levels in pa- tients hospitalized with coronavirus disease 2019. Nutrients. 2021;13(3).
  23. Kompaniyets L, Pennington AF, Goodman AB, Rosenblum HG, Belay B, Ko JY, et al. Underlying medical conditions and severe illness among 540,667 adults hospitalized with COVID-19, march 2020-march 2021. Prev Chronic Dis. 2021;18:E66.
  24. Hermel DJ, Spierling Bagsic SR, Costantini CL, Mason JR, Gahvari ZJ, Saven A. ABO phenotype and clinical correlates of COVID-19 severity in hospitalized patients. Fut Sci OA. 2021;7(8) Fso735.
  25. Bushman D, Davidson A, Pathela P, Greene SK, Weiss D, Reddy V, et al. Risk factors for death among hospitalized patients aged 21-64 years diagnosed with COVID- 19-New York City, March 13-April 9. J Racial Ethn health disparities. 2020;2021: 1-16.
  26. Pagano L, Salmanton-Garcia J, Marchesi F, Busca A, Corradini P, Hoenigl M, et al. COVID-19 infection in adult patients with Hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA). J Hematol Oncol. 2021;14(1):168.
  27. Chojnicki M, Neumann-Podczaska A, Seostianin M, Tomczak Z, Tariq H, Chudek J, et al. Long-term survival of older patients hospitalized for COVID-19 do clinical char- acteristics upon admission matter? Int J Environ Res Public Health. 2021;18(20).
  28. Bernardo J, Goncalves J, Gameiro J, Oliveira J, Marques F, Duarte I, et al. The impact of transient and persistent acute kidney injury in hospital mortality in COVID-19 pa- tients. Jornal brasileiro de nefrologia: ‘orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia; 2021.
  29. Alhasan KA, Shalaby MA, Temsah MH, Aljamaan F, Shagal R, AlFaadhel T, et al. Fac- tors that influence mortality in critically ill patients with SARS-CoV-2 infection: a multicenter study in the Kingdom of Saudi Arabia. Healthcare (Basel Switzerland). 2021;9(12).
  30. Kim YJ, Jee Y, Park S, Ha EH, Jo I, Lee HW, et al. Mortality risk within 14 days after coronavirus disease 2019 diagnosis in dementia patients: a Nationwide analysis. Dement Geriatr Cogn Disord. 2021;50(5):425-36.
  31. Buso G, Mazzolai L, Rueda-Camino JA, Fernandez-Capitan C, Jimenez D, Bikdeli B, et al. Pulmonary embolism in patients with COVID-19: comparison between differ- ent care settings. Semin Thromb Hemost. 2021. https://doi.org/10.1055/s-0041- 1740152. Epub ahead of print.
  32. AbuRuz S, Al-Azayzih A, ZainAlAbdin S, Beiram R, Al Hajjar M. Clinical characteristics and risk factors for mortality among COVID-19 hospitalized patients in UAE: does ethnic origin have an impact. PLoS One. 2022;17(3):e0264547.