Iron and B12 Deficiency Has Rarely Been Considered in Studies Defining Hemoglobin Concentration Reference Intervals in Pregnancy: A Systematic Review

Background: The World Health Organization (WHO) defines anemia in pregnancy with a hemoglobin concentration threshold of 110 g/L in the first and third trimesters, and 105 g/L in the second trimester. Pregnancy is characterized by increased demand for iron and vitamin B12, which often leads to deficiencies during this time. It is unclear if WHO and other pregnancy anemia thresholds have considered the impact of iron and B12 deficiency. Objective: The objectives were to systematically summarize healthy pregnancy hemoglobin concentration reference intervals, means and medians, and to conduct a quality assessment investigating whether studies defining anemia thresholds in pregnancy excluded people at high risk of or with iron and B12 deficiency. Methods: We developed a comprehensive search strategy designed to explore Medline, CINAHL, Embase, Web of and the gray literature from inception to March 2024, and included randomized controlled trials, retrospective, and prospective observational studies. All included studies were screened by two independent reviewers and adjudicated by a third when there was disagreement. Studies that defined hemoglobin reference intervals and normal values in a healthy pregnant population were included. A quality assessment was performed based on the Clinical and Laboratory Standards Institute (CLSI) guideline for establishing laboratory reference intervals, and clinical or laboratory evaluation of iron and B12 deficiency (such as bleeding history, dietary history, iron or B12 supplementation use, blood transfusion history, as well as measurement of mean corpuscular volume (MCV), serum ferritin or iron studies, and serum vitamin B12 levels). We used descriptive statistics, calculating proportions for categorical variables and medians for continuous variables, to summarize the data. Results: 5015 articles were initially identified, 366 were selected for full-text review, and 76 met inclusion criteria for detailed review, reporting a hemoglobin concentration reference interval, mean, or median. Among these, 45 studies aimed to define hemoglobin concentration reference intervals in healthy pregnant populations. 53% (24/45) of these studies did not adhere to CLSI guidelines for reference interval establishment. 56% (25/45) of studies did not exclude individuals with at least one clinical risk factor for iron deficiency, and 91% (41/45) did not exclude individuals with clinical risk factors for B12 deficiency. 91% (41/45) of the studies did not exclude pregnant people with laboratory evidence of iron deficiency. No studies excluded pregnant people with laboratory evidence of B12 deficiency. Of the 69 articles that aimed to define a normal mean or median hemoglobin concentration in a healthy pregnant population, 68% (47/69) did not exclude patients with at least one clinical risk factor for iron deficiency, and 96% (66/69) did not exclude those at risk for B12 deficiency. Additionally, 96% (66/69) of the studies did not exclude people with laboratory evidence of iron deficiency, and no study excluded people with laboratory evidence of B12 deficiency. The median lower limit of normal hemoglobin concentration reported in studies assessing reference intervals (n=45) was 109 g/L, 101 g/L, and 98 g/L for the first, second, and third trimesters, respectively. When evaluating the studies that met CLSI standards, the median lower limit of normal of hemoglobin concentration was 106 g/L in the first trimester, and 98 g/L in both the second and third trimesters. One study that met CLSI standards excluded individuals with laboratory evidence of iron deficiency. Conclusion: We found that iron and B12 deficiencies have largely not been accounted for when defining reference intervals and normal hemoglobin concentrations in presumed healthy pregnant people. This structurally decreases the opportunity to correct for maternal anemia -which is associated with severe maternal morbidity, maternal mortality and negative fetal, neonatal and childhood outcomes.

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