Presentation Details
| Iron deficiency has generally not been considered when defining sex-based hemoglobin reference intervals: A systematic review Ingrid Blydt-Hansen1, Vidushi Swarup2, Teruko Kishibe3, Carine Bekdache2, Vanessa Giuliano4, Rebecca Sampat2, Rowan Thillaye-Kerr2, Angela Weyand5, Mark Crowther6, Miranda Wozniak7, Grace H Tang8, Michelle Sholzberg8. 1Department of Internal Medicine, University of British Columbia, Vancouver, BC, Canada.2Hematology-Oncology Clinical Research Group, Division of Hematology-Oncology, St.Michael's Hospital, Toronto, Canada, Toronto, ON, Canada.3Health Sciences Library, St.Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto, ON, Canada.4Department of Medicine, University of Toronto, Toronto, ON, Canada.5Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.6Department of Medicine, McMaster University, Hamilton, ON, Canada.7Department of Laboratory Medicine & Pathobiology, Hematological Pathology, University of Toronto, Toronto, ON, Canada.8Departments of Medicine, and Laboratory Medicine and Pathobiology, St Michael’s Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada |
Abstract
Background: The World Health Organization defines anemia as a hemoglobin below 120 g/L for females and below 130 g/L for males. Historically, this discrepancy has been attributed to physiological differences between biological sexes. However, there is increasing evidence to suggest that sampled ‘healthy’ females for the establishment of hemoglobin reference intervals (RIs) included those with untreated iron deficiency. In fact, iron deficiency anemia is the most common presenting manifestation of bleeding disorders in females. Applying appropriate definitions of anemia are therefore of great importance to individuals with disorders of hemostasis and those on antithrombotic therapies given the prevalence of anemia and its association with morbidity and mortality. To address this, we conducted a systematic review to evaluate the literature to date on sex-based hemoglobin RIs. Objectives: To determine if healthy females without evidence of or risk factors for iron deficiency have a lower baseline hemoglobin than healthy males. Methods: A systematic review was conducted using a comprehensive search of MEDLINE, EMBASE, CINAHL and Web of Science from inception to November 2022. Two reviewers independently screened and performed data extraction. A third reviewer adjudicated decisions when a consensus was not reached. Studies that evaluated hemoglobin RIs in a state of known pathophysiology (e.g. untreated iron deficiency, bone marrow pathology, inherited red blood cell disorders, chronic diseases) were excluded. A priori defined quality assessment of all manuscripts was performed and included the following criteria: the manner in which “health” was defined in the sampled population, whether there was adherence to Clinical and Laboratory Standards (CLSI) guidelines for RI establishment studies, methodological rigour applied and transparent reporting of results. Results: 6411 articles were generated for title/abstract review, 909 articles were selected for full-text analysis. 313 articles met inclusion criteria and were extracted for analysis. 139 articles sought to establish a hemoglobin RI. The remainder (174/313) established a mean hemoglobin within the designated study population. Of the studies that sought to establish a RI, 66 adhered to CLSI guidelines (47%). 209/313 studies considered iron deficiency status and/or risk factors in study design (e.g. MCV, ferritin, bleeding history). 63/313 (20%) studies excluded individuals with laboratory evidence of and/or at least one risk factor for iron deficiency. Of the studies that used ferritin as the screening laboratory test for iron deficiency, the ranges of the lower limit of normal (LLN) for ferritin were as follows: 0-12.1 ug/L (31 studies), 13-15 ug/L (18 studies), 16-30 ug/L (14 studies) and 50 ug/L in 1. In the remaining 250 (80%) studies, individuals with iron deficiency and/or iron deficiency risk factors may have been included. Conclusion: Only 20% of studies evaluated explicitly excluded individuals with iron deficiency or its risk factors when establishing a hemoglobin RI or mean. Furthermore, in studies that measured ferritin, the majority used a ferritin LLN below established standards to define iron deficiency. This systematic review identifies that risk of iron deficiency and iron status are not routinely considered when establishing a hemoglobin RI, despite the extremely high prevalence of iron deficiency in females.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.