Identification and treatment of iron‐deficiency anemia in pregnancy and postpartum: A systematic review and quality appraisal of guidelines using AGREE II

Several international guidelines provide recommendations for the optimal management of iron‐deficiency anemia (IDA) in the pregnant and postpartum populations.


| INTRODUC TI ON
Anemia in pregnancy is a worldwide public health concern, with the World Health Organization estimating 40% of pregnant individuals globally to be anemic. 1Anemia is generally defined as a hemoglobin value less than 110 g/L, though trimester-and postpartum-specific criteria also exist. 2 During pregnancy, increased erythrocyte mass helps to meet the demands of placental perfusion. 3However, the increased plasma volume produces a dilutional effect, 4 resulting in "physiologic anemia".
Symptoms of anemia include fatigue, weakness, pre-syncope, syncope, and dyspnea. 1 The most common etiology of anemia in pregnancy is iron deficiency (ID), accounting for approximately 50%-60% of cases. 5ID and iron-deficiency anemia (IDA) in pregnancy have been associated with increased rates of adverse maternal outcomes, including pre-eclampsia, placenta previa, cesarean delivery, longer hospitalization, increased antenatal admission, and increased requirement for red blood cell transfusion. 6Maternal anemia in pregnancy has also been linked with important neonatal impacts, including preterm birth, small for gestational age, a low 5min Apgar score, and neonatal and perinatal death. 6,7In addition, non-anemic ID in pregnancy may impact long-term mental and psychomotor development in infants. 8on deficiency is typically multifactorial and can include decreased iron availability (including insufficient dietary iron intake or poor absorption) and/or increased losses (from vomiting or blood loss), and is compounded by increased iron demands during pregnancy. 9Consequently, it can be challenging for pregnant women to maintain adequate iron stores for the duration of their pregnancy without supplementation. 10on supplementation is a safe and cost-effective treatment for ID and IDA.Oral iron is the most common first-line option; however, it can be associated with gastrointestinal side effects, such as constipation, which can lead to poor adherence. 11When oral iron is not tolerated or is ineffective, the use of parenteral (intravenous) iron can be considered.Parenteral iron can quickly and effectively replenish iron stores and is indicated for severe IDA, in patients unable to tolerate oral iron, and/or if the patient is close to delivery.
Optimizing antenatal iron stores and hemoglobin can reduce the requirement for postpartum red blood cell transfusion. 12ven the adverse maternal and fetal outcomes associated with IDA in pregnancy, screening, diagnosis, and treatment are paramount.While many international guidelines exist, they differ in their recommendations, resulting in variations in the criteria for diagnosis and strategies for the management of anemia in pregnancy and postpartum.The objective of this study was to systematically evaluate relevant guidelines using AGREE II to appraise their quality and to compare and summarize the recommendations for the management of IDA in pregnancy and postpartum.

| Data sources and searches
A search for published guidelines was performed in PubMed, Medline, and Embase databases from database inception until August 2, 2021.Search terms included: pregnancy, prenatal care, pregnant individuals, IDA, guideline, and practice guideline.The full search strategy for each database is outlined in Table S1.In addition, the Google search engine was used to search for guidelines addressing IDA in pregnancy and postpartum.A forward and backward reference screen was conducted on selected guidelines to ensure no relevant articles were missed.

| Study selection
Included clinical practice guidelines focused on the management of anemia during the pregnancy and postpartum period.Clinical practice guidelines were defined as statements that included recommendations informed by evidence and experts in the field, which could be translated into clinical practice to improve the care of patients.Guidelines written in any language were included and translated to English using Google Translate.Guidelines were excluded if their publication type was not considered a clinical practice guideline (as defined above), if they lacked information on management of IDA, or if the target population did not comprise pregnant or postpartum women.In addition, if guidelines were updated, only the most recent version was included.

| Data extraction and quality assessment
Covidence software 13 was used to manage the screening process, starting with title and abstracts and progressing to full-text review, which was conducted independently by two reviewers.All guidelines meeting the inclusion criteria were subjected to quality assessment by two independent reviewers, with resolution of conflict by consensus.

| AGREE II quality assessment
The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was used to assess guideline quality. 14 Each AGREE II item was ranked using a seven-point scale.A score of one indicated strong disagreement with the concept and was typically given when the guideline held no information relevant to the item or when the item was insufficiently reported.A score of seven indicated strong agreement with the item and was given when the guideline fully and exceptionally met the criteria and considerations for that item.
Scores between two and six were assigned when the guidelines met some but not all of the criteria and/or considerations for a specific item.other published literature and the AGREE II user manual, a domain score of 70% or higher denoted high-quality. 15,16 overall score for each guideline was assigned through consensus among the reviewers.Guidelines were given an overall score of one to seven: a score of one indicated a weak guideline and seven indicated an exceptional guideline.Reviewers determined an overall score for each guideline based on domain scores (where all domains were given equal prioritization), and a subjective overall impression.
In addition, guidelines were either recommended, recommended with modifications, or not recommended.

| Synthesis and analysis of guideline content
Key and specific recommendations on the management of IDA in pregnancy and the postpartum period were extracted from each guideline based on the following clinically relevant topics: routine iron supplementation, screening for IDA, diagnosis of ID, oral iron treatment, parenteral iron treatment, other treatment options, and monitoring of treatment response.For each topic, recommendations were coded as follows: recommended for, recommended with restrictions (defined as a recommendation that is applicable only in specific circumstances, situations, or patient sub-population), recommended against, and insufficient evidence to make a recommendation.

| Reviewer agreement
Inter-rater agreement, which evaluates the extent of agreement between the two independent reviewers, was described as a percentage.Cohen's κ was used to report inter-rater reliability based on the following categories: 0, no agreement; 0.01-0.20,none to slight agreement; 0.21-0.40,fair agreement; 0.41-0.60,moderate agreement, 0.61-0.80,substantial agreement, and 0.81-1.00,almost perfect agreement. 17

| RE SULTS
The database search and the forward and backward citation screen identified a total of 2887 citations after 502 duplicates were removed (Figure 1).Following title and abstract screening, 114 full texts were reviewed, and 16 guidelines were included: 12 (75%) from the literature search and four (25%) from the Google search.
Characteristics of included guidelines are summarized in Table S3.

| Quality appraisal
The quality assessment using AGREE II is described in Table S4.
Overall agreement between the reviewers was 48%, with a Cohen's κ of 0.45, indicating moderate inter-rater reliability. 17 Regarding the overall assessment, six (37.5%) of the guidelines were deemed high quality (score of six or seven) and were recommended by the reviewers.The remaining guidelines scored a four or five in the overall score and were recommended with modifications, except for one which was not recommended because of a financial conflict of interest.

| Content synthesis and analysis of guidelines
Recommendations on anemia management in pregnancy and postpartum from each guideline are indicated in Table S5.Specific details on each recommendation set out by each guideline for IDA management in pregnancy and postpartum are outlined in Tables 2 and   3, respectively.A summary of all recommendations across included guidelines are described in Table 4.

Routine iron supplementation
Universal iron supplementation was recommended in six (37.5%) guidelines.Prenatal vitamins typically contain 30 mg of elemental iron, which is the recommended target dose in the ACOG, 18 BCG, 19 CDC, 20 and FIGO 21 guidelines, whereas higher doses of universal iron supplementation were recommended by WHO (30-60 mg/ day) 22 and FOGSI (60-100 mg/day). 23NATA guidelines recommend targeted iron supplementation only for pregnant women who live in areas with a high prevalence of anemia. 24Conversely, four (25%) guidelines recommend against routine universal iron supplementation, [25][26][27][28] as high doses of oral iron can be associated with negative effects on mineral absorption and oxidative pathways and other issues including gastrointestinal adverse effects. 29 note, once ID/IDA is diagnosed, the content of iron in prenatal vitamins is not sufficient to correct the deficiency and an additional dedicated iron supplement is required. 30,31

Screening and diagnosis
Screening for anemia in pregnancy is performed with a complete blood count, and 11 (75%) guidelines recommended routine universal screening of all patients in each pregnancy.Recommendations around the timing of screening included the first booking appointment, 20,25 with additional screening in the late second trimester, 18,21,24,28 or in every trimester. 22,26,32The USPSTF guidelines report insufficient evidence to make a recommendation on routine screening for anemia in pregnancy in asymptomatic patients. 33garding diagnosis, pregnancy-specific hemoglobin cut-offs have been proposed to account for the large increase in plasma volume during pregnancy and subsequent dilutional "physiologic anemia". 334,35 The Asia-Pacific guidelines use a cut-off of less than 105 g/L, 36 and FIGO and NATA guidelines use less than 110 g/L, 21,24 each irrespective of trimester.Hematocrit values can also be used as diagnostic criteria for anemia, with values less than 33%, less than 32%, and less than 33% in the first, second, and third trimesters, respectively. 18,20,26ce anemia is identified, the diagnosis of ID is typically performed with serum ferritin.Serum ferritin has a sensitivity of 90% and specificity of 85% in the diagnosis of ID in pregnant women; 37 however, given its role as an acute-phase reactant, it can be falsely elevated in patients with active inflammation or infection.In these cases, transferrin saturation may be required to clarify the diagnosis. 38 TA B L E 2 Details of guideline recommendations for the management of anemia in pregnancy.

Diagnosis of anemia
define ID, [18][19][20]22,26,28,33,35 while others recommended a cut-off of less than 15 μg/L. 20,26 The utilzation of different biochemical parameters and thresholds to reflect iron stores creates inconsistency and confusion among providers.39 Currently, no guidelines recommend unselected ferritin testing for all pregnant women.
The UK guideline suggests screening for ID by risk factors on history, including patients with a history of anemia, multiples, short interpregnancy interval, those at risk for inadequate dietary iron (e.g.vegetarian, adolescents), and those at risk of bleeding during pregnancy or delivery (including patients who are Jehovah's Witnesses). 35

Treatment
Once diagnosed, IDA should be treated with oral iron, with guidelines recommending a dosage of 40-200 mg of elemental iron per day.
[34][35][36] An adequate response to oral iron is defined as an increase in hemoglobin by 10 or 20 g/L in 2 or 4 weeks, respectively.Longer-term reassessment can be considered every 8 weeks throughout pregnancy 25 and every 3 months for 1 year. 26Once hemoglobin has normalized, four (25%) guidelines recommend continuing oral iron treatment for at least 3 months or 6 weeks postpartum, whichever is longer 21,24,28,35 to ensure adequate iron repletion.
Parenteral iron is a safe and effective way to rapidly replenish iron stores in pregnancy and is noted to be more effective than oral iron preparations in correcting anemia with fewer gastrointestinal side effects. 40Parenteral iron should be considered in cases where oral iron is ineffective, 21,24,25,28,[34][35][36] the individual is intolerant or experiences malabsorption (e.g., patients with a history of gastric surgery or conditions such as inflammatory bowel disease which can interfere with oral iron absorption), 18,21,[24][25][26]28,32,34,35 the individual is non-compliant, 34,36 or the anemia is severe. 18,25,36 Paenteral iron is not advised during the first trimester 18,19,21,24,[34][35][36] because of a lack of safety data.41

Postpartum management
Ten (62.5%) guidelines included discussion around the management of IDA postpartum.No guidelines recommend universal screening for postpartum anemia.One (6%) guideline recommended screening for anemia before delivery, 24 whereas others recommended screening in the early postpartum period in patients who either experienced excessive blood loss during delivery, 20,24,25,28,34,35 were in poor clinical condition, 25,28,32,34,35 or had uncorrected antepartum anemia. 20,28,32,34,35st guidelines defined postpartum anemia as hemoglobin less than 100 g/L. 24,25,28,35,36Alternative definitions included hemoglobin less than 110 g/L, 21 and less than 120 g/L. 20,32,34[36] Similar to antenatal recommendations, postpartum patients with IDA should be monitored with repeat hemoglobin in 2-4 weeks following treatment commencement, with an expected 10-20 g/L increase, respectively. 20,24,365][36] In contrast, DSOG guidelines provided a conditional recommendation against the use of parenteral iron for the treatment of anemia during the postpartum period. 25 cases of hemodynamic instability, significant symptomatic anemia, or where there is a risk of further bleeding or cardiac compromise, 21,[23][24][25]28,35,36 blood transfusion should be considered, but must be balanced with the risk of alloimmunization and transfusion reaction.  Univers iron supplementation is recommended for all pregnant women by six (37.5%) guidelines 19,21,22,25,26,34 2.
Eleven (69%) guidelines recommended routine screening for anemia in pregnancy.Recommendations around timing of screening include the first booking appointment, 22,23 with or without additional screening in the late second trimester, 25,27,29,32 or in every trimester. 24,30,34USPSTF guidelines report insufficient evidence to make a recommendation on routine screening for anemia in pregnancy 33 3. Hemoglobin <110 g/L in the first and third trimesters or <105 g/L in the second trimester were the most universally common definitions of anemia in pregnancy. 19,22,24,30,31,34Serum ferritin with a value <30 μg/L is generally considered as the diagnostic criterion for iron deficiency, 19,21,27,[29][30][31][32] whereas others recommended ferritin <15 μg/L 22,23 4.
One (6%) guideline recommended routine iron supplementation for 6-12 weeks postpartum in individuals who live in areas where anemia is highly prevalent 27 2.
0][31][32] One (6%) guideline provided a conditional recommendation against the use of parenteral iron for the treatment of anemia postpartum 23 6.
Blood transfusion was advised in cases of hemodynamic instability, significant symptomatic anemia, or in cases where there is a risk of further bleeding or cardiac compromise 20,23,[25][26][27]29,32 Abbreviations: IDA, iron-deficiency anemia; USPSTF, United States Preventive Services Task Force.
postpartum populations, with clear objectives regarding diagnostic criteria and recommendations for management.
Issues around generalizability and implementation were common.This is reflected in the lowest scoring domains: Stakeholder Involvement and Applicability, with only two (13%) guidelines deemed high-quality in these domains.Many guidelines were lacking adequate involvement of key stakeholders, including narrow authorship representation, and limited patient and/or public perspective.The complex interplay between race, ethnicity, socioeconomic status, and coexistent nutritional deficiencies was often not addressed, and these issues cannot be ignored when considering population-based recommendations, given that IDA affects a disproportionate number of minoritized people, with the highest rates found in Black, Hispanic, and Indigenous populations. 43For example, in North America, Black patients face a two-fold higher rate of IDA in pregnancy compared with non-Hispanic White patients.The prevalence of IDA climbs to nearly 50% of Black patients in the third trimester, and rates are rising. 44though the cause of racial and ethnic disparities is unclear, coexistent socioeconomic variables, including social conditions, 45 food insecurity, and intergenerational inequalities in health can be complexly intertewined to propagate poorer outcomes in marginalized populations.Similar patterns are seen globally, where the prevalence of IDA in low-income countries is three to four times the prevalence seen in high-income countries. 46When recommendations fail to take race, ethnicity, and other important socioeconomic variables into account, guidelines can subsequently limit their generalizability, as was demonstrated in this study.
Many guidelines failed to identify barriers to implementation of the clinical recommendations, strategies to improve uptake, and importantly, did not address resource and cost implications of the recommendations.Despite the association between IDA and poor maternal and fetal outcomes, there is limited prospective evidence demonstrating the impact of population-based iron supplementation programs in reducing IDA and its associated consequences.
Evidence is limited by many additional issues, such as availability of and access to supplementation, and poor patient compliance with treatment. 46Creative solutions are required to address these issues.
These could include optimizing pre-pregnancy iron stores, identification and treatment of non-anemic ID, and adoption of alternative dosing regimens. 47productive-aged non-pregnant females have high rates of ID, with rates described from 8.8% to 36%. 48Preconception anemia has been associated with an increased risk of adverse pregnancy outcomes, reduced infant growth, 49 and increased rates of childhood anemia. 50Preconception iron supplementation (vs delaying supplementation until after pregnancy has been established) resulted in improved maternal iron stores in pregnancy and postpartum, and improved neonatal iron stores. 51Targeting interventions to the preconception period may assist in reducing the rates of IDA and subsequent complications in pregnancy and postpartum.
Similarly, earlier detection and treatment of non-anemic ID in pregnancy provides an opportunity to intervene and treat earlier in the pathway of the development of IDA.Up to 52% of pregnant women have ID at some point in pregnancy, with only 8.3% noted to have IDA. 45Patients with non-anemic ID would not be identified with current screening strategies, which focus on hemoglobin alone, and would only be detected with expanded routine assessment of iron stores (i.e.routine ferritin or transferrin saturation measurements).In addition, emerging evidence from animal models suggests a critical role for iron in the development of the fetal brain, 52 and ID in neonates is associated with cognitive and behavioral abnormalities that can persist despite iron repletion. 53Universal screening for non-anemic ID is cost-effective compared with no screening or targeted screening in other populations, 39 and its utility in pregnant women should be explored.Earlier identification of non-anemic ID will allow an opportunity to identify and correct ID earlier in pregnancy, and potentially avoid the long-term consequences of fetal development in an ID milieu.
The issue of patient adherence remains a pressing barrier.One of the simplest and most effective ways of improving adherence is using alternate day (every other day) dosing protocols, which have been shown to result in effective iron replenishment with fewer adverse effects. 54Future studies aimed at improving compliance and access to iron supplementation (both oral and parenteral) in the populations identified at highest risk will help to address this gap.
Although AGREE II is a widely used framework designed to assess clinical practice guideline quality and has been endorsed by numerous healthcare organizations, 14 it is not without limitations.For each item, the AGREE II tool includes a "How to Rate" description, providing criteria and considerations to take into account when scoring; however, it does not objectively link criteria with a numerical score, and therefore subjectivity is consequential.Further, the overall impression lacks instruction on how to determine a final score or if the guideline should be recommended.These areas of subjectivity within the AGREE II framework may explain the moderate inter-rater variability in this study.
This study provides an evaluation and summary of contemporary guidelines in the diagnosis and management of IDA in pregnancy and the postpartum period.We identified ongoing areas of improvement for guideline development in this population.This summary can be used to facilitate the development of local or regional protocols aimed at improving the identification of patients affected by IDA while highlighting current barriers, challenges, and population-specific considerations that need to be addressed.

AUTH O R CO NTR I B UTI O N S
Victoria Mintsopoulos, Evan Tannenbaum, and Melissa Walker wrote the protocol; Victoria Mintsopoulos screened and selected eligible studies and extracted data; Victoria Mintsopoulos and Melissa Walker independently scored each study using AGREE II.Any difference of opinion was discussed between Victoria This instrument addresses important components of guidelines including their methodologies, comprehensiveness, and transparency, and whether they are user-friendly for the rater.AGREE II comprises 23 items that are organized into six domains: Scope and Purpose, Stakeholder Involvement, Rigor of Development, Clarity of Presentation, K E Y W O R D S clinical practice guidelines, iron-deficiency anemia, postpartum, pregnancy Applicability, and Editorial Independence.The assessment concludes with an overall rating.Table S2 describes each domain and item assessed by AGREE II (https://www.agreetrust.org/).
Two reviewers independently scored AGREE II items for each guideline.The documented score for each item was summed within its respective domain and included the minimum and maximum scores.The scaled domain score was determined by the following calculation: ([obtained score − minimum possible score]/[maximum possible score − minimum possible score]) × 100%.Consistent with

2. 7 |
Role of funding sourceThis review was funded by the Sinai Health Clinicians in Quality Improvement Award at Mount Sinai Hospital in Toronto, Canada.This funding body had no role in any aspect of the study, including study design, guideline identification, result interpretation, or approval of this article. FIGO24

TA B L E 3
Abbreviations: -, not mentioned; BID, twice daily; ESA, erythropoiesis-stimulating agents; Hb, hemoglobin; Hct, hematocrit; IDA, iron-deficiency anemia; IV, intravenous; PP, postpartum; SF, serum ferritin; T1, first trimester; T2, second trimester; T3, third trimester; Guidelines: ACOG, The American College of Obstetricians and Gynecologists; BCG, British Columbia Guidelines; CDC, Centers for Disease Control and Prevention; DSOG, Danish Society of Obstetrics and Gynecology; FEMECOG, Federación Mexicana de Colegios de Obstetricia y Ginecología; FIGO, International Federation of Gynecology and Obstetrics; FOGSI, The Federation of Obstetric and Gynecological Societies of India; NATA, Network for the Advancement of Patient Blood Management, Hemostasis and Thrombosis; NICE, National Institute for Health and Care Excellence; SAMNCP, South Australian Maternal and Neonatal Community of Practice; SSGO, Swiss Society of Gynecology and Obstetrics; UK, United Kingdom; USPSTF, United States Preventive Services Task Force; WHO, World Health Organization.

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Abbreviations: -, not mentioned; CBC, BID, twice daily; complete blood count; Hb, hemoglobin; Hct, hematocrit; PP, postpartum; SF, serum ferritin; Guidleins: CDC, Centers for Disease Control and Prevention; DSOG, Danish Society of Obstetrics and Gynecology; FIGO, International Federation of Gynecology and Obstetrics; FOGSI, The Federation of Obstetric and Gynecological Societies of India; NATA, Network for the Advancement of Patient Blood Management, Hemostasis and Thrombosis; SAMNCP, South Australian Maternal and Neonatal Community of Practice; SSGO, Swiss Society of Gynecology and Obstetrics; UK, United Kingdom.

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DISCUSS IONThis systematic review, following the AGREE-II appraisal method, identified 16 guidelines focusing on the management of anemia during pregnancy and postpartum.Six (37.5%) were recommended by reviewers, as they satisfied the quality criteria for most domains in this appraisal.The remainder were not recommended because of low scores in various quality criteria, including Stakeholder Involvement and Applicability.Many guidelines received high quality scores (>70%) in the domains of Scope and Purpose and Clarity of Presentation.This was reflected in the clarity of the aim and specific questions addressed by the guideline.There was also consensus regarding the widespread and pervasive issue of IDA in pregnant and TA B L E 4 Summary of recommendations on the management of iron-deficiency anemia in pregnancy and postpartum (n = 16 guidelines).Pregnancy1.