Skip to navigation bar Skip to breadcrumbs Skip to page content
clear place holder
Envelope icon E-mail Updates Teal square Text size:  a A A

Evidence Summary

Other Supporting Document for Iron Deficiency Anemia in Pregnant Women: Screening and Supplementation

Preface

By Amy G. Cantor, MD, MPH; Christina Bougatsos, MPH; Tracy Dana, MLS; Ian Blazina, MPH; and Marian McDonagh, PharmD


The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was published online first at www.annals.org on March 31, 2015.

Abstract

Background: Routine screening and supplementation for iron deficiency anemia (IDA) in asymptomatic, nonanemic pregnant women could improve maternal and infant health outcomes.

Purpose: Update of a 2006 systematic review by the U.S. Preventive Services Task Force on screening and supplementation for IDA in pregnancy.

Data Sources: MEDLINE and the Cochrane Library (1996 to August 2014) and reference lists of relevant systematic reviews to identify studies published since 1996.

Study Selection: English-language trials and controlled observational studies about effectiveness of screening and routine supplementation for IDA in developed countries.

Data Extraction: Data extraction and quality assessment confirmed and dual-rated by a second investigator using prespecified criteria.

Data Synthesis: No study directly compared clinical outcomes or harms of screening or not screening pregnant women for IDA. Twelve supplementation trials were included, and no controlled observational studies met inclusion criteria. On the basis of 11 trials, routine maternal iron supplementation had inconsistent effects on rates of cesarean delivery, small size for gestational age, and low birthweight and no effect on maternal quality of life, gestational age, Apgar scores, preterm birth, or infant mortality. Twelve trials reported improvements in maternal hematologic indices, although not all were statistically significant. Pooled analysis of 4 trials resulted in a statistically significant difference in IDA incidence at term, favoring supplementation (risk ratio, 0.29 [95% CI, 0.17 to 0.49]; I2 = 0%). Maternal iron supplementation did not affect infant iron status at 6 months. Harms, none of which were serious or had long-term consequences, were inconsistently reported in 10 of the trials, with most finding no difference between groups.

Limitation: Data from trials in countries with limited generalizability to U.S. populations were included. Studies were methodologically heterogeneous, and some were small and underpowered.

Conclusion: There is inconclusive evidence that routine prenatal supplementation for IDA improves maternal or infant clinical health outcomes, but supplementation may improve maternal hematologic indices.

Primary Funding Source: Agency for Healthcare Research and Quality.

Introduction

Iron deficiency is the most common pathologic cause of anemia in pregnancy. Increased risk during pregnancy is due to increased maternal iron needs and demands from the growing fetus and placenta; increased erythrocyte mass; and, in the third trimester, expanded maternal blood volume.1–5 Definitions of iron deficiency anemia (IDA) in pregnant women may be imprecise given pregnancy-associated physiologic changes and variable definitions in population subgroups.1, 2 Physiologic anemia, or dilutional anemia of pregnancy, is common in healthy pregnant women due to blood volume expansion to support the growing fetus and is associated with a modest decrease in hemoglobin levels. Iron deficiency occurs when the level of stored iron becomes depleted. Iron deficiency anemia occurs when iron levels are sufficiently depleted to produce anemia.1, 6 Serum ferritin is useful in diagnosing iron deficiency in pregnant women, who can have an elevated serum transferrin level in the absence of iron deficiency. As an acute-phase reactant, serum ferritin can be elevated in inflammatory conditions and may be of limited usefulness when concentrations decrease late in pregnancy.7

Overall prevalence of iron deficiency in pregnant women in the United States is near 18%, with anemia in 5% of pregnant women and rates of iron deficiency increasing across trimesters from 6.9% to 14.3% to 28.4%.5 Risk factors for iron deficiency or IDA in pregnant women include an iron-deficient diet, gastrointestinal issues affecting absorption, or a short pregnancy interval.8 Pregnant women with clinically significant iron deficiency or IDA may present with fatigue, weakness, pallor, tachycardia, and shortness of breath.9 Maternal iron requirements average 1000 mg/d.10 Because many pregnant women lack sufficient iron stores, iron supplementation may be included in prenatal care. Primary prevention for average-risk populations includes adequate intake of dietary iron and oral, low-dose (30 mg/d) iron supplements early in pregnancy.11 Suggested prophylaxis for IDA in high-risk populations is 60 to 100 mg of elemental iron daily.12

The association between iron status and negative outcomes for women and their infants is inconclusive. Although many older observational studies, including uncontrolled and cross-sectional studies, have shown an association between various measures of iron status and negative perinatal outcomes, such as low birthweight,13–15 premature birth,13–18 and perinatal death,14 more rigorous trial evidence is inconsistent. Screening for IDA may lead to earlier identification and earlier treatment, which may prevent serious negative health outcomes.

The U.S. Preventive Services Task Force (USPSTF) last reviewed evidence on prenatal screening for IDA in 2006 and recommended routine screening (B recommendation) on the basis of fair-quality evidence.19 There was insufficient evidence (no studies) on the accuracy of screening in asymptomatic pregnant women but fair-quality evidence that treating asymptomatic IDA in pregnancy results in moderate health benefits. Evidence was also insufficient to recommend for or against routine iron supplementation for nonanemic pregnant women (I statement).

This review was commissioned by the USPSTF to update the prior recommendations.19 We examined evidence from U.S.-relevant populations on the effectiveness of routine supplementation and screening for IDA in pregnancy.

Methods

Methods are described in detail in a technical report.20 On the basis of evidence gaps identified from prior reviews,21, 22 and in consultation with the USPSTF,23 we developed key questions and analytic frameworks for routine supplementation (Appendix Figure 1) and screening (Appendix Figure 2) for IDA during pregnancy. Key questions were as follows.

Supplementation

  1. What are the benefits of routine iron supplementation in pregnant women on maternal and infant health outcomes?
  2. What are the harms of routine iron supplementation in pregnant women?

Screening

  1. What are the benefits of screening asymptomatic pregnant women for iron deficiency anemia on maternal and infant health outcomes?
  2. What are the harms of screening for iron deficiency anemia in pregnant women?
  3. What are the benefits of treatment for iron deficiency anemia in pregnant women on maternal and infant health outcomes?
  4. What are the harms of iron treatment in pregnant women?
  5. What is the association between a change in maternal iron status (including changes in ferritin or hemoglobin level) and improvement in newborn and peripartum outcomes in U.S.-relevant populations?

Data Sources

We searched the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE (1996 to August 2014) (Appendix Table 1). We also searched reference lists of relevant systematic reviews to identify studies published before 1996, the year that the prior reviews concluded.

Study Selection

Abstracts were selected for full-text review if they included asymptomatic pregnant women receiving screening or supplementation for IDA, were relevant to a key question, and met predefined inclusion criteria.20 For the screening framework, key questions focused on the effectiveness of screening compared with not screening in preventing adverse health outcomes and reducing the incidence of complications, as well as the association of improvements in intermediate and clinical health outcomes with harms (including infant harms). Health outcomes included long- or short-term maternal and infant morbidity (including birth outcomes), infant mortality, and maternal quality of life (including postpartum depression) resulting from screening, supplementation, or treatment and related harms. Intermediate outcomes included iron status based on hematologic indices, including ferritin levels. Additional outcomes included the relationship between a change in maternal iron status and maternal and infant health outcomes. We focused on studies using iron supplementation and treatment regimens commonly used in clinical practice in the United States and those conducted in countries with "high" or "very high" human development based on the United Nations Human Development Index.24 We included only English-language articles and excluded studies published as abstracts or without original data. Two reviewers independently evaluated each study to determine inclusion eligibility. We included randomized, controlled trials; nonrandomized, controlled trials; and cohort studies for all key questions. When good- and fair-quality studies were available, poor-quality studies were excluded. The selection of studies is summarized in Figure 1.

Data Extraction and Quality Rating

One investigator abstracted details about study design, patient population, setting, screening method, analysis, follow-up, and results. A second investigator reviewed the data abstraction for accuracy. Using predefined criteria developed by the USPSTF,23 2 investigators rated the quality of studies (good, fair, or poor)23 and resolved discrepancies by consensus.

Data Synthesis and Analysis

We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) by using methods developed by the USPSTF, based on the number, quality, and size of studies; consistency of results among studies; and directness of evidence.23

Meta-analysis was performed when studies were available that used comparable dosages, durations, and timing of outcome assessment. We conducted meta-analyses using the Mantel–Haenszel random- or fixed-effects models in Review Manager, version 5.2 (Cochrane Collaboration), to calculate risk ratios of the effects of routine iron supplementation on incidence of preterm delivery, low birthweight, and maternal IDA and iron deficiency at term. Statistical heterogeneity was assessed using the I2 statistic. Due to methodological shortcomings in the studies and differences across studies in design, interventions (timing and dosing), patient populations, and other factors, meta-analysis was not attempted for all outcome measures.

Role of the Funding Source

This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues arising during the project; and finalize the report. AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. AHRQ performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication.

Results

Effectiveness of Routine Iron Supplementation in Pregnancy

We identified a total of 12 good-quality25–27 and fair-quality28–36 trials comparing the effects of routine prenatal iron supplementation versus no supplementation.37, 38 Studies were conducted in the United States, Iran, Hong Kong, Australia, and Europe. Sample sizes ranged from 45 to 1164 participants, although only 2 studies had more than 500.27, 28 Most studies reported that women with significantly low hematologic indices at baseline were excluded from the study and received treatment.25–29, 31–33, 35 Several studies also reported providing treatment if indices dropped too low during the study.25–28, 31, 33 The majority of enrolled women were in their 20s, and most were white or black (or race was not reported). Two of the 3 studies that were conducted in the United States29, 32 were in women at higher risk for anemia on the basis of reported risk factors (such as eligibility for the Special Supplemental Nutrition Program for Women, Infants, and Children; black race; or parity >2). All other included studies were of women at average risk for anemia; however, risk factors were not always reported, and no studies stratified results by risk groups.

The timing of supplementation varied from the first prenatal visit to 20 weeks' gestation and continued until delivery. However, in 2 studies conducted in the United States, participants in the placebo group were reassigned to supplementation at 26 to 29 weeks' gestation; therefore, results up to that time are included in this report.29, 32 Outcomes were measured in the third trimester or at delivery, or studies included a short duration of follow-up into the postpartum period. Supplement dosing ranged from 20 to 200 mg of elemental iron daily. Adherence, usually based on pill counts or an equation involving pill counts, was variably reported but ranged from 54% to 98%.

Only 5 of the included studies (in 6 publications) reported power or sample size calculations.25, 27–29, 32, 37 Two studies were powered to detect reductions in the rate of anemia (from 30% to 15%29 and from 25% to 15%32). One of these studies was also powered to detect between-group differences of 0.407 times the SD of birthweight and gestational age.29 One study was powered to detect reductions in rates of IDA (from 11.5% to 3%) and iron deficiency (from 30% to 15%) and an increase in rates of gastrointestinal adverse effects (from 10% to 20%).25 The sample size of 1 study was calculated to detect a 7% difference in the proportion of infants born small for their gestational age,27 and another study enrolled enough patients to detect an increase in the incidence of gestational diabetes from 10% to 15%.28

Maternal Clinical Outcomes

Quality of life was reported as a secondary outcome in a good-quality trial (n = 430) that found no clear differences between women receiving iron supplementation versus placebo in any of the 8 Short Form-36 health concepts during pregnancy or after delivery.25

Cesarean delivery may occur for various indications, including elective ones, and has no known causal relationship with IDA. However, it is typically considered a measurable clinical outcome in pregnancy and was reported in 5 trials as an ad hoc event.25, 27, 28, 31, 35 These trials of average-risk women compared groups of pregnant women receiving or not receiving iron supplementation. Reported rates of cesarean delivery ranged from 7.6% to 26% in the supplementation groups and from 9.1% to 33% in the placebo groups.25, 27, 28, 31, 35 One large fair-quality trial (n = 1164) from Hong Kong found a significant reduction in the rate of cesarean delivery for women receiving 60 mg of elemental iron daily versus placebo (25.2% vs. 33.1%; odds ratio, 0.58 [95% CI, 0.37 to 0.89]; P = 0.008).28 However, findings from 4 smaller fair- and good-quality trials (n = 97 to 727) on the effect of supplementation on rates of cesarean delivery for women receiving 20, 50, or 60 mg of elemental iron supplementation versus placebo were inconclusive.25, 27, 31, 35

Infant Clinical Outcomes

A total of 11 good-quality25, 27 and fair-quality28–36 trials reported infant birth outcomes, including mortality, preterm delivery, length of gestation, small size for gestational age, birthweight, and Apgar scores (Appendix Table 2).

Four trials25, 27, 31, 35 of pregnant women at average risk for anemia anecdotally reported no clear effect of prenatal iron supplements on infant mortality, with rates of 0% to 1.9% in the supplementation groups and 0% to 1.7% in the placebo groups, although this was not a prespecified outcome in these studies. One good-quality Iranian trial reported no difference in rates of perinatal mortality for supplementation versus placebo (0.8% vs. 1.7%).27

Four fair-quality trials conducted in Hong Kong, the United States, and Iran reported rates of preterm delivery (defined as delivery at <37 weeks) ranging from 3% to 12.8% in the supplementation groups and from 6.8% to 13.9% in the placebo groups.28–30, 32 Consistent with the prior report, these trials found no statistically significant difference between exposure to routine prenatal iron supplementation and rates of preterm delivery compared with placebo. Pooling estimates from 2 studies28, 30 that provided 60 mg of elemental iron as supplemental dosing also resulted in a non–statistically significant difference in the incidence of preterm birth in the supplementation groups (risk ratio [RR], 0.88 [CI, 0.55 to 1.42]; I2 = 0%) compared with placebo (Figure 2).

Six fair-quality trials and 1 good-quality trial reported no effect of maternal iron supplementation on length of gestation, with all studies reporting gestational ages between 38 and 40 weeks for participants in the supplementation and placebo groups.25, 28–32, 36 Two of the studies were conducted in the United States and included women at higher risk for iron deficiency.

Three fair-quality trials and 1 good-quality trial conducted in Hong Kong, the United States, and Iran reported inconsistent findings for infants exposed to prenatal iron supplementation who were small for their gestational age (defined as below the 10th percentile of birthweight for their gestational age), with ranges of 3.6% to 15% for those in the supplementation groups and 7.5% to 17.7% for those in the placebo groups.27–29, 32 A trial conducted in Hong Kong of women at average risk for anemia and a trial conducted in the United States of women at higher risk for iron deficiency reported fewer infants who were small for their gestational age among women in the supplementation group versus the placebo group (3.6% vs. 7.5% [P = 0.013]28 and 6.8% vs. 17.7% [P = 0.014]29). Another U.S. trial of women at higher risk for iron deficiency reported no difference between the supplementation and placebo groups (10.8% vs. 15.5% [P = 0.22]).32 One good-quality Iranian trial of women at average risk for anemia found that those not receiving supplementation had significantly fewer infants who were small for their gestational age (15% vs. 10% [P = 0.035]).27

Six trials (5 fair-quality and 1 good-quality) conducted in the United States, Iran, Ireland, and Australia that reported the incidence of infants born with low birthweight (defined mostly as <2500 g) found inconsistent results. Incidence of low birthweight ranged from 0% to 9.4% in the supplementation groups and from 0% to 16.7% in the placebo groups.25, 29–32, 35 One U.S. trial of women at higher risk for iron deficiency (n = 275) found significantly lower rates of low-birthweight infants in the supplementation group versus the placebo group (4.3% vs. 16.7% [P = 0.003]).29 However, 5 trials, including a separate U.S. trial of women at higher risk for iron deficiency, found no effect of prenatal iron supplementation on the rate of low-birthweight infants.25, 30–32, 35 Pooled analysis of 3 comparable studies25, 30, 31 that used supplementation with 20 to 60 mg of elemental iron resulted in a non–statistically significant relative risk of 1.10 (CI, 0.54 to 2.25; I2 = 0%) compared with placebo (Figure 3).

In 8 trials reporting mean infant birthweight, all infants had birthweight within the normal range, and 5 trials found no difference among participants receiving supplementation versus placebo.25, 30, 33, 34, 36 Three other trials found that women receiving placebo had infants with lower mean birthweight (3247 vs. 3151 g [P = 0.001],28 3277 vs. 3072 g [P = 0.010],29 and 3325 vs. 3217 g [P = 0.03]32).

Five trials (4 fair-quality and 1 good-quality) reported Apgar scores at 1, 5, or 10 minutes and found no difference in scores between infants exposed to routine maternal iron supplementation versus placebo.25, 27, 28, 31, 36

Maternal Intermediate Outcomes

Consistent with the prior reports,21, 22 12 good or fair-quality trials reported improvement in maternal hematologic indices with variable doses of iron supplementation versus placebo at various time points and used variable definitions of hematologic indices, although not all improvements were statistically significant (Appendix Table 3).25–36 The clinical significance of these findings is unclear. We report results at term because this was the most consistently reported and, possibly, the most clinically relevant time point. Results for the third trimester and various postpartum time points are detailed in Appendix Table 3 and in the full report.20

Six trials reported incidence of IDA (defined as hemoglobin level <110 g/L and serum ferritin level <27 or <44.9 pmol/L), with overall ranges of 0% to 12.7% for women in the supplementation groups and 0% to 29% for those in the placebo groups in the third trimester, at delivery, or after delivery.25, 29–32, 34 One good quality (n = 430) and 1 fair-quality (n = 120) trial reported a significantly lower incidence of IDA at term in pregnant women receiving routine iron supplementation versus placebo (3% vs. 11%; RR, 0.28 [CI, 0.12 to 0.68]25 and 0% vs. 17.5% [P = 0.02]34). However, 2 smaller fair-quality trials found no difference between groups, with one reporting incidence of 0% in both groups30 and the other reporting incidence of 5% versus 29% for adolescents (P = 0.137) and 10.5% versus 22.2% for adults (P = 0.259).31 Pooled analysis of 4 comparable trials resulted in a statistically significant difference between groups in incidence of IDA at term, favoring supplementation (RR, 0.29 [CI, 0.17 to 0.49]; I2 = 0%) (Figure 4).25, 30, 31, 34

Six trials reported incidence of iron deficiency (defined as serum ferritin level <27, <33.7, or <44.9 pmol/L). Overall ranges were 0% to 56% for women in the supplementation groups and 28% to 85% for those in the placebo groups, with consistent results across measurement time points; however, not all results reached statistical significance.25, 29, 30, 32, 33, 36 At term, 3 trials (2 fair-quality and 1 good-quality) found lower rates of iron deficiency at delivery for women receiving supplementation (9.5% vs. 28.2% [P < 0.05],30 35% vs. 58%; RR, 0.60 [CI, 0.48 to 0.76],25 and 0% vs. 65.2% [P = 0.02].36 Pooled results of 2 trials with comparable dosing regimens (20 to 60 mg of elemental iron daily) indicated a statistically significant difference in iron deficiency at term that favored supplementation (RR, 0.53 [CI, 0.33 to 0.84]; P = 0.006; I2 = 40%) (Figure 4).25, 30

Four trials reported incidence of anemia (defined as hemoglobin level <100 or <110 g/L), with overall ranges of 3.7% to 21% for women in the supplementation groups and 4.5% to 27% for those in the placebo groups.25, 29, 32, 33 At term, 1 good-quality trial reported a significantly lower incidence of anemia at delivery for pregnant women receiving routine iron supplementation versus placebo (7% vs. 16%; RR, 0.45 [CI, 0.25 to 0.82]).25

Eleven good- or fair-quality trials of women receiving iron supplementation versus placebo reported hemoglobin levels in the third trimester, at delivery, or up to 6 months after delivery, with overall ranges of 114 to 139 g/L for those in the supplementation groups and 113 to 134 g/L for those in the placebo groups.25–32, 34–36 At term, 8 trials found that women receiving supplementation had higher hemoglobin levels at delivery than those receiving placebo, although results were statistically significant in only 6.25, 26, 28, 31, 34, 35

Ten trials reported serum ferritin levels in the third trimester, at delivery, or up to 6 months after delivery, with values ranging from 16.6 to 76.4 pmol/L for women receiving supplementation and from 13.5 to 58.4 pmol/L for those receiving placebo.25, 26, 28–32, 34–36 Five trials of women at average risk for anemia found that those receiving supplementation had significantly higher serum ferritin levels at term than those receiving placebo.25, 26, 28, 31, 34

Infant Intermediate Outcomes

A 6-month follow-up study to a good-quality Australian trial25 of 336 infants, in which mothers at 20 weeks' gestation were randomly allocated to receive 20 mg of elemental iron supplementation daily until delivery, was the only study reporting infant hematologic outcomes and found no differences in iron status of children at 6 months.

Harms of Routine Iron Supplementation in Pregnancy

Harms of routine iron supplementation in pregnant women were sparsely and variably reported, often as ad hoc events, in 10 good- or fair-quality trials comparing iron supplementation with placebo. None of the harms were serious or associated with long-term significance, and there were mostly no significant differences between groups (Appendix Table 4).25, 27–33, 35, 36

Two trials conducted in Australia and the United States reported no differences in various minor gastrointestinal adverse effects between supplementation (60 and 20 mg of elemental iron daily, respectively) and placebo.25, 31 Four studies from Australia, the United States, and Norway reported no significant differences in rates of any adverse event and no differences in adherence or discontinuation of supplementation.25, 29, 31, 33 Harms were measured after at least 1 clinic visit through 36 weeks and included general medication adverse effects, fatigue, or any adverse event. Additional reporting on related maternal harms was limited and inconsistent. There was no relationship between supplementation and maternal hypertension27, 30 or gestational diabetes.28

Screening for IDA

No studies met inclusion criteria for any of the key questions on benefits and harms of screening for IDA in pregnancy, benefits and harms of screen-detected treatment, or the association between a change in maternal iron deficiency or IDA status and improvement in newborn and peripartum outcomes in U.S.-relevant populations.

Discussion

A summary of the evidence is presented in the Table. Newer evidence identified for this review is consistent with findings from the previous USPSTF reviews21, 22 and shows that iron supplementation is often effective in improving maternal hematologic indices and may result in a lower incidence of women with iron deficiency and IDA during pregnancy and at delivery. However, evidence is insufficient to demonstrate a substantial effect on clinical outcomes for women and infants. No study directly compared clinical outcomes or harms of screening or not screening pregnant women for IDA.

In this updated review, 12 trials compared the effects of routine prenatal iron supplementation versus no supplementation, and 11 reported various clinical outcomes for women and infants. No controlled observational studies met inclusion criteria. One trial reported no difference in quality of life for pregnant women receiving iron supplementation versus placebo. Trials of prenatal iron supplementation found no clear effect on infant gestational age, Apgar scores, preterm birth, or infant mortality; however, infant mortality was not a prespecified outcome. Findings were inconsistent among studies reporting an effect of maternal iron supplementation on rates of cesarean delivery, small size for gestational age, and low birthweight. Of note, the strength of this evidence was reduced by the small number of trials reporting these outcomes (for example, 5 trials reporting on premature birth, small size for gestational age, and cesarean delivery); the combined lack of power in these studies; and methodological heterogeneity, which prevented pooling of studies and determination of consistency and study quality. As such, meta-analysis was not performed for all outcomes. These findings are similar to those of recent Cochrane reviews that compared daily and intermittent oral iron supplementation or assessed iron treatment during pregnancy in trials conducted mostly in developing countries.11, 39– 41 These reviews found overall methodologically poor evidence showing no effect on infant outcomes, including low birthweight and preterm birth.

The strongest evidence supporting a benefit of supplementation on hematologic outcomes was from a good-quality, Australian randomized trial of pregnant women at average risk for anemia25 that reported improvements in some maternal hematologic parameters. Eleven other good- or fair-quality trials26–36 supported the evidence that maternal iron supplements may improve hematologic parameters or reduce the incidence of IDA, but the clinical significance of the findings is unclear. One follow-up study of maternal iron supplementation during pregnancy reported no differences in iron status of children at age 6 months.37 No studies reported serious harms resulting from supplementation.

We excluded non–English-language articles, which could have resulted in language bias, although no such studies meeting inclusion criteria at the abstract level were identified. We could not formally assess for publication bias with graphical or statistical methods because of small numbers of pooled studies or inability to pool studies. Although all study locations met criteria for at least high human development on the United Nations Human Development Index,24 some studies included data that may not be generalizable to the United States due to differences in such factors as nutritional status, resources, and health care infrastructure. Study populations included mostly women at average risk for IDA or did not report risk level, except for 2 of the 3 U.S. studies29, 32 that included women at higher risk for anemia based on reported risk factors (such as eligibility for the Special Supplemental Nutrition Program for Women, Infants, and Children29, 32 or black race32). Results may differ for high-risk populations, especially in the United States. However, both of these studies ended the placebo phase of the trial at 28 weeks' gestation, after which all women in the study received routine iron supplementation, thereby limiting the interpretation of trial results.

Better research is needed to identify the long-term clinical health effects of routine iron supplementation during pregnancy in developed countries. Infants exposed to prenatal iron supplementation should continue to be followed to identify unexpected or emerging long-term benefits or harms from maternal supplementation. Research is needed to understand the clinical significance of the short-term improvement in maternal hematologic outcomes after prenatal iron supplementation and the nuances of supplementation dose and timing, as well as to strengthen conclusions by more consistently examining the effect on clinical maternal and infant outcomes in large, high-quality studies.

In summary, routine iron supplementation during pregnancy may improve maternal hematologic indices and reduce the incidence of iron deficiency and IDA in the short term. However, there is no clear or consistent evidence that prenatal iron supplementation has a beneficial clinical impact on maternal or infant health. In addition, no trials are available on the effect of prenatal screening for IDA on clinical outcomes despite routine screening practices in many high-income countries. Rigorous studies are needed to fully understand the short- and long-term effect of routine iron supplementation and screening during pregnancy on women and infants, including the effects on rates of cesarean delivery, small size for gestational age, and low birthweight. Until then, the evidence on routine iron supplementation and screening in prenatal care will remain unclear at best.

Copyright and Source Information

Disclaimer: The investigators are solely responsible for the content of this article and the decision to submit it for publication. The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.

Source: This article was published online first at www.annals.org on March 31, 2015.

Financial Support: Ms. Bougatsos reports that this manuscript is based on a larger review funded by the Agency for Healthcare Research and Quality. Ms. Dana reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Mr. Blazina reports support from the Agency for Healthcare Research and Quality for a larger report upon which this manuscript is based.

Potential Conflicts of Interest: Authors not named here have disclosed no conflicts of interest. Disclosures can be viewed at www.acponline.org/authors/icmje/Conflict OfInterestForms.do?msNum=M14-2932.

Requests for Single Reprints: Reprints are available from the Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mail Code BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098.

References

1. Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47:1-29. [PMID: 9563847]
2. Earl R, Woteki CE, eds. Iron Deficiency Anemia: Recommended Guidelines for the Prevention, Detection, and Management Among U.S. Children and Women of Childbearing Age. Washington, DC: National Academies Press; 1993.
3. Krishnamurti L. Part 9: Iron-deficiency anemia. In: McInerny TK, Adam HM, Campbell DE, Kamat DM, Kelleher KJ, eds. American Academy of Pediatrics Textbook of Pediatric Care. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
4. Scholl TO. Iron status during pregnancy: setting the stage for mother and infant. Am J Clin Nutr. 2005;81:1218S-1222S. [PMID: 15883455]
5. Mei Z, Cogswell ME, Looker AC, Pfeiffer CM, Cusick SE, Lacher DA, et al. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999– 2006. Am J Clin Nutr. 2011;93:1312-20. [PMID: 21430118]
6. Griffin IJ, Abrams SA. Iron and breastfeeding. Pediatr Clin North Am. 2001;48:401-13. [PMID: 11339160]
7. World Health Organization. Iron Deficiency Anaemia: Assessment, Prevention and Control. A Guide for Programme Managers. Geneva: World Health Organization; 2001. Accessed at www.who.int /nutrition/publications/en/ida_assessment_prevention_control.pdf on 6 February 2015.
8. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 95: anemia in pregnancy. Obstet Gynecol. 2008;112:201-7. [PMID: 18591330]
9. Hoffman R, Benz EJ, Silberstein LE, Heslop H, Weitz J, Anastasi J. Hematology: Basic Principles and Practice. 6th ed. Philadelphia: Elsevier Saunders; 2012.
10. Bothwell TH. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr. 2000;72:257S-264S. [PMID: 10871591]
11. Pe a-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Intermittent oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2012;7:CD009997. [PMID: 22786531]
12. World Health Organization. Iron and Folate Supplementation. Standards for Maternal and Neonatal Care. Integrated Management of Pregnancy and Childbirth (IMPAC). Volume 1.8. Geneva: World Health Organization; 2006.
13. Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr. 1992;55:985-8. [PMID: 1570808]
14. Murphy JF, O'Riordan J, Newcombe RG, Coles EC, Pearson JF. Relation of haemoglobin levels in first and second trimesters to outcome of pregnancy. Lancet. 1986;1:992-5. [PMID: 2871331]
15. Zhou LM, Yang WW, Hua JZ, Deng CQ, Tao X, Stoltzfus RJ. Relation of hemoglobin measured at different times in pregnancy to preterm birth and low birth weight in Shanghai, China. Am J Epidemiol. 1998;148:998-1006. [PMID: 9829872]
16. Klebanoff MA, Shiono PH, Selby JV, Trachtenberg AI, Graubard BI. Anemia and spontaneous preterm birth. Am J Obstet Gynecol. 1991;164:59-63. [PMID: 1986627]
17. Lu ZM, Goldenberg RL, Cliver SP, Cutter G, Blankson M. The relationship between maternal hematocrit and pregnancy outcome. Obstet Gynecol. 1991;77:190-4. [PMID: 1988879]
18. Singh K, Fong YF, Arulkumaran S. Anaemia in pregnancy—across-sectional study in Singapore. Eur J Clin Nutr. 1998;52:65-70. [PMID: 9481535]
19. U.S. Preventive Services Task Force. Recommendation statement: screening for iron deficiency anemia—including iron supplementation for children and pregnant women. Rockville, MD: U.S. Preventive Services Task Force; 2006.
20. McDonagh M, Cantor A, Bougatsos C, Dana T, Blazina I. Routine iron supplementation and screening for iron deficiency anemia in pregnant women: a systematic review to update the U.S. Preventive Services Task Force recommendation. Evidence Synthesis no. 123. AHRQ Publication no. 13-05188-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
21. DiGuiseppi C, ed. Screening for Iron Deficiency Anemia—Including Iron Prophylaxis. Guide to Clinical Preventive Services: Report of the U.S. Preventive Services Task Force. 2nd ed. Baltimore: Williams & Wilkins; 1996.
22. Oregon Evidence-based Practice Center. Screening for iron deficiency anemia in childhood and pregnancy: update of the 1996 U.S. Preventive Services Task Force review. Evidence Synthesis no. 40. AHRQ Publication no. 06-0590-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2006.
23. U.S. Preventive Services Task Force. Procedure Manual. Rockville, MD: U.S. Preventive Services Task Force; 2008. Accessed at http://www.uspreventiveservicestaskforce.org/Page/Name/procedure-manual on 26 March 2015.
24. United Nations Development Programme. Human Development Index (HDI)—2012 Rankings. United Nations Development Programme; 2014. Accessed at http://hdr.undp.org/en/statistics on 6 February 2015.
25. Makrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM. Efficacy and tolerability of low-dose iron supplements during pregnancy: a randomized controlled trial. Am J Clin Nutr. 2003;78:145- 53. [PMID: 12816784]
26. Ziaei S, Mehrnia M, Faghihzadeh S. Iron status markers in nonanemic pregnant women with and without iron supplementation. Int J Gynaecol Obstet. 2008;100:130-2. [PMID: 17977537]
27. Ziaei S, Norrozi M, Faghihzadeh S, Jafarbegloo E. A randomised placebo-controlled trial to determine the effect of iron supplementation on pregnancy outcome in pregnant women with haemoglobin > or = 13.2 g/dL. BJOG. 2007;114: 684-8. [PMID: 17516958]
28. Chan KK, Chan BC, Lam KF, Tam S, Lao TT. Iron supplement in pregnancy and development of gestational diabetes—a randomised placebo-controlled trial. BJOG. 2009;116:789-97. [PMID: 19432567]
29. Cogswell ME, Parvanta I, Ickes L, Yip R, Brittenham GM. Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. Am J Clin Nutr. 2003;78:773-81. [PMID: 14522736]
30. Falahi E, Akbari S, Ebrahimzade F, Gargari BP. Impact of prophylactic iron supplementation in healthy pregnant women on maternal iron status and birth outcome. Food Nutr Bull. 2011;32:213-7. [PMID: 22073795]
31. Meier PR, Nickerson HJ, Olson KA, Berg RL, Meyer JA. Prevention of iron deficiency anemia in adolescent and adult pregnancies. Clin Med Res. 2003;1:29-36. [PMID: 15931282]
32. Siega-Riz AM, Hartzema AG, Turnbull C, Thorp J, McDonald T, Cogswell ME. The effects of prophylactic iron given in prenatal supplements on iron status and birth outcomes: a randomized controlled trial. Am J Obstet Gynecol. 2006;194:512-9. [PMID: 16458655]
33. Eskeland B, Malterud K, Ulvik RJ, Hunskaar S. Iron supplementation in pregnancy: is less enough? A randomized, placebo controlled trial of low dose iron supplementation with and without heme iron. Acta Obstet Gynecol Scand. 1997;76:822-8. [PMID: 9351406]
34. Milman N, Agger AO, Nielsen OJ. Iron status markers and serum erythropoietin in 120 mothers and newborn infants. Effect of iron supplementation in normal pregnancy. Acta Obstet Gynecol Scand. 1994;73:200-4. [PMID: 8122498]
35. Barton DP, Joy MT, Lappin TR, Afrasiabi M, Morel JG, O'Riordan J, et al. Maternal erythropoietin in singleton pregnancies: a randomized trial on the effect of oral hematinic supplementation. Am J Obstet Gynecol. 1994;170:896-901. [PMID: 8141223]
36. Romslo I, Haram K, Sagen N, Augensen K. Iron requirement in normal pregnancy as assessed by serum ferritin, serum transferrin saturation and erythrocyte protoporphyrin determinations. Br J Obstet Gynaecol. 1983;90:101-7. [PMID: 6824608]
37. Zhou SJ, Gibson RA, Makrides M. Routine iron supplementation in pregnancy has no effect on iron status of children at six months and four years of age. J Pediatr. 2007;151:438-40. [PMID: 17889086]
38. Milman N, Agger AO, Nielsen OJ. Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled study in 207 Danish women. Dan Med Bull. 1991;38:471-6. [PMID: 1802636]
39. Pe a-Rosas JP, Viteri FE. Effects and safety of preventive oral iron or iron+folic acid supplementation for women during pregnancy. Cochrane Database Syst Rev. 2009:CD004736. [PMID: 19821332]
40. Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2011:CD003094. [PMID: 21975735]
41. Cuervo LG, Mahomed K. Treatments for iron deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2001:CD003094. [PMID: 11406073]

Figure 1. Summary of evidence search and selection.


KQ = key question.
* Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews.
† Prior reports, reference lists of relevant articles, and systematic reviews.
‡ Some studies are included for >1 KQ.
§ Poor-quality studies were excluded because good- and fair-quality evidence was available.

Text Description.

This figure is a literature flow diagram depicting the search and selection of studies for the present review. The diagram shows that 1,431 abstracts of potentially relevant articles were identified through the MEDLINE and Cochrane databases, 1,148 articles and background papers were excluded, 283 articles were reviewed at the full-text level, and 269 articles were excluded for the following reasons: 61 due to wrong population, 21 due to wrong intervention, 12 due to wrong outcome, 44 due to wrong study design, 41 due to wrong publication type, 6 due to non-English language, 57 due to wrong comparison, 11 were systematic reviews that were not directly used, and 16 due to poor-quality for supplementation Key Question 1. 12 unique trials (in 14 publications) were ultimately included in the review. For the Routine Iron Supplementation section of the report, for Key Question 1, 5 trials were included for maternal clinical outcomes, 11 trials were included for infant birth outcomes, and 12 trials were included for hematological outcomes. For Key Question 2, 10 trials were included on harms of supplementation. For the Screening for Iron Deficiency Anemia section of the report, no studies were included for any of the Key Questions

Figure 2. Meta-analysis: preterm delivery.


M–H = Mantel–Haenszel.

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effects of routine iron supplementation on incidence of preterm delivery were calculated for two studies (Chan 2009 and Falahi 2011), with a pooled risk ratio of 0.88 (95% CI, 0.55 to 1.42) and overall heterogeneity of 0%.

Figure 3. Meta-analysis: low birthweight.


M–H = Mantel–Haenszel.

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effects of routine iron supplementation on incidence of low birthweight were calculated for three studies (Falahi 2011, Makrides 2003, and Meier 2003 [separate adult and adolescent populations]), with a pooled risk ratio of 1.10 (95% CI, 0.54 to 2.25) and overall heterogeneity of 0%.

Figure 4. Meta-analysis: iron deficiency anemia and iron deficiency at term.

* Includes 2 studies that used 20- and 60-mg dosing. Reference 36 was excluded from the analysis because the study used 200-mg dosing. M–H = Mantel–Haenszel.

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effects of routine iron supplementation on incidence of maternal iron deficiency anemia at term were calculated for four studies (Falahi 2011, Makrides 2003, Meier 2003 [separate adult and adolescent populations], and Milman 1994), with a pooled risk ratio of 0.29 (95% CI, 0.17 to 0.49) and overall heterogeneity of 0%. For the Iron Deficiency section: risk ratios of the effects of routine iron supplementation on incidence of maternal iron deficiency at term were calculated for three studies (Falahi 2011, Makrides 2003, Romslo 1983), with a pooled risk ratio of 0.53 (95% CI, 0.33 to 0.84) and overall heterogeneity of 40%.

Table. Summary of Evidence

Outcome, by Key Question Primary Findings From Prior USPSTF Reviews Studies Identified for Update Limitations Consistency Applicability Summary of Findings Overall Quality*
Routine iron supplementation in pregnant women
What are the benefits of routine iron supplementation in pregnant women on maternal and infant health outcomes?
Maternal clinical outcomes Limited evidence showing improved clinical outcomes 5 RCTs Outcomes reported mostly as ad hoc events; variable doses of iron supplements Consistent Studies limited to those done in U.S.-relevant countries and populations 1 trial reported no differences in quality of life between pregnant women receiving iron supplementation and those receiving placebo.
5 trials reported rates of cesarean delivery. 1 trial found significantly fewer cesarean deliveries in women receiving iron supplementation, whereas 4 trials of women receiving 20, 50, or 60 mg of elemental iron supplementation versus placebo were inconclusive
Poor
Infant clinical outcomes
Mortality Limited evidence; 1 trial reported fewer infant deaths in the selective supplementation group 4 trials Outcomes reported mostly as ad hoc events; variable doses of iron supplements Consistent 1 trial done in Iran 4 trials reported no clear effect of prenatal iron supplementation on infant mortality Poor
Preterm delivery Limited evidence showing no effect on pregnancy outcomes 4 RCTs Variable doses of iron supplements Consistent No issues 4 studies found no association between prenatal iron supplementation and incidence of preterm delivery Fair
Length of gestation Limited evidence showing no effect on pregnancy outcomes 6 RCTs Variable doses of iron supplements Consistent No issues 6 trials reported no effect of maternal iron supplementation on length of gestation. All studies reported gestational ages between 38 and 40 wk for infants in both the supplementation and placebo groups Fair
Small size for gestational age No studies 4 RCTs Variable doses of iron supplements Inconsistent No issues 4 trials reported inconsistent findings for small size for gestational age Fair
Low birthweight Limited evidence showing no effect on pregnancy outcomes 6 RCTs Variable doses of iron supplements Inconsistent No issues 1 U.S. trial of higher-risk women reported significantly lower rates of low-birthweight (<2500 g) infants exposed to prenatal iron supplementation (4.3% vs. 16.7%; P = 0.003). 5 studies, including a separate U.S. trial of higher-risk women, found no effect of prenatal iron supplementation on the rate of low-birthweight infants Fair
Apgar scores No studies 5 RCTs Variable doses of iron supplements Consistent No issues 5 trials found no difference in Apgar scores at 1 and 5 min in infants exposed to prenatal iron supplements versus placebo Fair
Maternal intermediate outcomes Iron supplements are effective in improving maternal hematologic indices 12 RCTs for intermediate outcomes Variable doses of iron supplements Consistent Studies limited to those done in U.S.-relevant countries and populations 12 trials reported improvement in maternal hematologic indices with variable doses of iron supplementation versus placebo but inconsistent associations between iron supplementation and incidence of maternal iron deficiency or anemia. Pooled analysis of 4 comparable trials (20 to 66 mg of iron daily) found a statistically significant between-group difference in incidence of iron deficiency anemia at term, favoring supplementation (RR, 0.29 [95% CI, 0.17 to 0.49]; I2 = 0%). The clinical significance of these findings is unclear Fair
Infant intermediate outcomes Not assessed 1 follow-up study No issues NA No issues 1 study reported infant hematologic outcomes as a follow-up to the good-quality Australian trial; mothers were randomly allocated to receive 20 mg of elemental iron daily from 20 wk of gestation until delivery. No difference was found in iron status of infants at age 6 mo Poor
What are the harms of routine iron supplementation in pregnant women?
  Reversible GI symptoms associated with iron use 10 RCTs Outcomes reported mostly as ad hoc events; variable doses of iron supplements Inconsistent No issues Harms of routine iron supplementation in pregnant women were sparsely and variably reported in 10 trials comparing iron supplementation versus placebo. None of the harms were serious or associated with long-term significance, and there were mostly no significant differences between groups. Reported harms included transient treatment effects (nausea, constipation, and diarrhea). Findings on rates of maternal hypertension were inconsistent. 6 trials found no between-group difference in nonadherence to supplementation versus placebo; 1 trial had lower nonadherence in the supplementation group than in the placebo group Poor
Screening for iron deficiency anemia in pregnant women
What are the benefits of screening asymptomatic pregnant women for iron deficiency anemia on maternal and infant health outcomes?
  No studies None NA NA NA NA NA
What are the harms of screening for iron deficiency anemia in pregnant women?
  No studies None NA NA NA NA NA
What are the benefits of treatment for iron deficiency anemia in pregnant women on maternal and infant health outcomes?
  Iron supplements are effective in improving maternal hematologic indices, but limited evidence exists showing improved clinical outcomes None NA NA NA NA NA
What are the harms of iron treatment in pregnant women?
  Reversible GI symptoms associated with iron use None NA NA NA NA NA
What is the association between a change in maternal iron status (including changes in ferritin or hemoglobin level) and improvement in newborn and peripartum outcomes in U.S.-relevant populations?
  Not reviewed None NA NA NA NA NA

GI = gastrointestinal; NA = not applicable; RCT = randomized, controlled trial; RR = risk ratio; USPSTF = U.S. Preventive Services Task Force.
* Based on new evidence identified for this update plus previously reviewed evidence.

Appendix Figure 1. Analytic framework for routine iron supplementation in pregnant women.

KQ = key question.

Key Questions

  1. What are the benefits of routine iron supplementation in pregnant women on maternal and infant health outcomes?
  2. What are the harms of routine iron supplementation in pregnant women?

Text Description.

This figure depicts the analytic framework, which outlines the evidence areas covered in the review, including the populations, interventions and related harms, and outcomes. The population includes pregnant women who are asymptomatic for iron deficiency anemia. After routine iron supplementation, and the assessment of any harms of routine supplementation, an arrow leads to the outcomes included in the review. Intermediate outcomes include various measure of iron status. A dotted line leads from the intermediate outcomes to the clinical outcomes examined, which include maternal and infant morbidity and mortality, including birth outcomes and quality of life. In addition, an overarching arrow from routine supplementation to the health outcomes of interest represents the direct effect of supplementation on these health outcomes.

Appendix Figure 2. Analytic framework for screening for iron deficiency anemia in pregnant women.

KQ = key question.

Key Questions

  1. What are the benefits of screening asymptomatic pregnant women for iron deficiency anemia on maternal and infant health outcomes?
  2. What are the harms of screening for iron deficiency anemia in pregnant women?
  3. What are the benefits of treatment for iron deficiency anemia in pregnant women on maternal and infant health outcomes?
  4. What are the harms of iron treatment in pregnant women?
  5. What is the association between a change in maternal iron status (including changes in ferritin or hemoglobin level) and improvement in newborn and peripartum outcomes in U.S.-relevant populations?

Text Description.

This figure depicts the analytic framework, which outlines the evidence areas covered in the review, including the populations, intervention and related harms, and outcomes. The population includes pregnant women who are asymptomatic for iron deficiency anemia. After screening, and the assessment of any harms of screening, a box represents the diagnosis of iron deficiency anemia. An arrow leading from this box represents treatment, after which the outcomes included in the review are indicated. Intermediate outcomes include various measure of iron status. A dotted line leads from the intermediate outcomes to the health outcomes examined, representing the association between intermediate and health outcomes. Health outcomes include maternal and infant morbidity and mortality, including birth outcomes and quality of life. A subsequent arrow from treatment examines the resulting harms of treatment. In addition, an overarching arrow from screening to the health outcomes of interest represents the direct effect of screening on these health outcomes.

Appendix Table 1. Search Strategies

Supplementation KQ1 and KQ2
   Database: Ovid MEDLINE(R) without revisions

1 exp Anemia, Iron-Deficiency/
2 "iron deficiency anemia".mp.
3 ("ida" or ("iron deficiency" adj2 "anemia")).mp.
4 or/1-3
5 pc.fs.
6 Dietary Supplements/
7 Iron/
8 6 and 7
9 (iron adj2 supplemen$).mp.
10 Iron, Dietary/ad
11 or/8-10
12 4 and 5
13 4 and 11
14 12 or 13
15 limit 14 to humans
16 limit 15 to english language
17 limit 15 to abstracts
18 exp Pregnancy/
19 pregnan$.mp.
20 18 or 19
21 17 and 20

Database: EBM Reviews - Cochrane Central Register of Controlled Trials
1 exp Anemia, Iron-Deficiency/
2 "iron deficiency anemia".mp.
3 ("ida" or ("iron deficiency" adj2 "anemia")).mp.
4 or/1-3
5 pc.fs.
6 Dietary Supplements/
7 Iron/
8 6 and 7
9 (iron adj2 supplemen$).mp.
10 Iron, Dietary
11 or/8-10
12 4 and 5
13 4 and 11
14 12 or 13
15 exp Pregnancy/
16 pregnan$.mp.
17 15 or 16
18 14 and 17

Screening KQ1 and KQ2
   Database: Ovid MEDLINE(R) without revisions

1 exp Anemia, Iron-Deficiency/
2 "iron deficiency anemia".mp.
3 ("ida" or ("iron deficiency" adj2 "anemia")).mp.
4 or/1-3
5 exp Mass Screening/
6 screen$.mp.
7 5 or 6
8 4 and 7
9 Pregnancy/
10 pregnan$.mp.
11 9 or 10
12 8 and 11
13 limit 8 to ("all adult (19 plus years)" or "adolescent (13 to 18
years)")
14 12 or 13
15 limit 14 to humans
16 limit 15 to english language
17 limit 15 to abstracts
18 16 or 17

Database: EBM Reviews - Cochrane Central Register of Controlled Trials
1 exp Anemia, Iron-Deficiency/
2 "iron deficiency anemia".mp.
3 ("ida" or ("iron deficiency" adj2 "anemia")).mp.
4 or/1-3
Appendix Table 1—Continued
5 exp Mass Screening/
6 screen$.mp.
7 5 or 6
8 4 and 7
9 Pregnancy/
10 pregnan$.mp.
11 9 or 10
12 8 and 11

Treatment KQ3 and KQ4
   Database: Ovid MEDLINE(R) without revisions

1 exp Anemia, Iron-Deficiency/
2 "iron deficiency anemia".mp.
3 ("ida" or ("iron deficiency" adj2 "anemia")).mp.
4 or/1-3
5 (de or dt or th).fs.
6 Iron/ or Iron, Dietary/
7 4 and (5 or 6)
8 exp Pregnancy/
9 pregnan$.mp.
10 7 and (8 or 9)
11 limit 10 to (english language and humans)

Database: EBM Reviews - Cochrane Central Register of Controlled Trials
1 exp Anemia, Iron-Deficiency/
2 "iron deficiency anemia".mp.
3 ("ida" or ("iron deficiency" adj2 "anemia")).mp.
4 or/1-3
5 (de or dt or th).fs.
6 Iron/ or Iron, Dietary
7 4 and (5 or 6)
8 exp Pregnancy/
9 pregnan$.mp.
10 7 and (8 or 9)

Association KQ5
   Database: Ovid MEDLINE(R) without revisions

1 Iron/
2 Iron, Dietary/
3 Anemia, Iron-Deficiency/
4 1 or 2
5 4 and (anemia or anemic or deficiency or deficient).mp.
6 3 or 5
7 Treatment Outcome/
8 6 and 7
9 6 and association.mp.
10 8 or 9
11 limit 10 to humans
12 limit 11 to english language

Systematic reviews – all KQs
   Database: EBM Reviews - Cochrane Database of Systematic Reviews

1 iron deficiency anemia.mp.
2 ("iron deficiency" adj2 anemia).mp.
3 1 or 2
Iron deficiency without anemia

Database: Ovid MEDLINE(R) without revisions
1 Iron/df [Deficiency]
2 Pregnancy Complications, Hematologic/ or Pregnancy
3 1 and 2
4 limit 3 to humans

Database: EBM Reviews - Cochrane Central Register of Controlled Trials
1 Iron/df [Deficiency]
2 Pregnancy Complications, Hematologic/ or Pregnancy/
3 1 and 2

EBM = Evidence-Based Medicine; KQ = key question.

Appendix Table 2. Infant Birth Outcomes*

Study, Year, Country, N, Quality Iron Supplement Dose, Formulation, and Initiation Risk Factors Reported Supplementation vs. Control
Apgar Score Preterm Delivery (<37 wk) Length of Gestation Small Size for Gestational Age (<10th Percentile of Birthweight for Gestational Age) Birthweight Low Birthweight (<2500 g) Infant Mortality
Barton 199435
Ireland n=97
Fair
120 mg elemental iron daily starting at 14 wk of gestation Race: NR (Ireland)
Nulliparous: 45%-47%
          <2700 g: 0.4% vs. 15.9%; P=0.34 1.9% vs. 0%; P=0.57
Chan 200928
Hong Kong n=1164
Fair
60 mg elemental iron daily starting at <16 wk of gestation Race: NR (Hong Kong)
Parity ≥2: 0.50% vs. 0.18%
BMI: 20.8 vs. 21.0 kg/m2
Score at 1 min: 8.8 vs. 8.8; P=NS
Score at 5 min: 9.8 vs. 9.7; P=NS
6.4% vs. 6.8%; P=0.85 39 vs. 39 wk; P=0.322 3.6% vs. 7.5%; P=0.013 3247.3 vs. 3151.9 g; P=0.001    
Cogswell 200329
United States n=275
Fair
30 mg elemental iron daily starting at <20 wk of gestation Race: White 56%-57%, black 24%-26%, Hispanic 16%-17%
Parity ≥2: 31% vs. 24%
High school education or less: 73%-76%
SES: 100% eligible for WIC
  12.8% vs. 12.5%; P=0.944 38.9 vs. 38.3 wk; P=0.05 6.8% vs. 17.7%; P=0.014 3277 vs. 3072 g; P=0.010 4.3% vs. 16.7%; P=0.003  
Eskeland 199733
Norway n=90
Fair
27 mg elemental iron daily starting at 20 wk of gestation Race: NR (Norway)
BMI: 22-23 kg/m2
Parity ≥2: 0%-10%
Single: 3%-17%
Low education: 3%-10%
        3690 vs. 3620 vs. 3610 g; P=NS    
Falahi 201130
Iran
n=148
Fair

 

60 mg elemental iron daily starting at <20 wk of gestation Race: NR (Iran)
BMI: 24-25 kg/m2
  3% vs. 6.8%; P=NS 38.9 vs. 38.8 wk; P=NS   3310 vs. 3270 g; P=NS 3% vs. 6.8%; P=NS  
Makrides 200325
Australia n=430
Good
20 mg elemental iron daily starting at 20 wk of gestation Race: White 95%, Aboriginal 0.9%-3.3%, Asian 1.4%-2.3%
Multiparous: 52%-53%
BMI: 26 kg/m2
Highest level of education: Year <10: 12%-15%, year 11: 27%- 28%, year 12: 28%-33%, trade certificate or diploma: 5%-8%, tertiary degree: 21%
Score <7 at 5 min: 1.4% vs. 1.5%; P=NS   39 vs. 39 wk; P=NS   3406 vs. 3449 g; P=NS 5.4% vs. 4.2%; P=NS 0.5% (1 case) vs. 0%; P=NS (infant born at 22 wk with bilateral intrauterine pneumonia)
Meier 200331
United States n=111
Fair
60 mg elemental iron daily starting at first prenatal visit Race: NR (Wisconsin)
Private group practice
Score <7 at 1 min: Adolescents 30% vs. 25%; P=NS
Adults 29.7% vs. 16.7%; P=NS
  Adolescents 39.9 vs. 39.8 wk; P=NS
Adults 39.2 vs. 39.5 wk; P=NS
    Adolescents 0% vs. 0%; P=NS
Adults 5.4% vs. 2.9%; P=NS
0% vs. 0%; P=NS
Milman 199434
Denmark n=120
Fair
66 mg elemental iron daily starting at 14-16 wk of gestation Race: NR (Denmark)         3350 vs. 3450 g; P=NS (median)    
Romslo 198336
Norway n=45
Fair
200 mg elemental iron daily starting within 10 wk of gestation Race: NR (Norway) 1-min score: 8.7 vs. 8.8; P=NR
5-min score: 9.0 vs. 9.0; P=NR
  39.9 vs. 39.5 wk; P=NR   3546 vs. 3510 g; P=NR    
Siega-Riz 200632
United States n=429
Fair
30 mg elemental iron daily starting at <20 wk of gestation Race: Black 58%-65%, White 31%-37%
Single: 75%
Parity ≥2: 44% vs. 41%
SES: 100% eligible for WIC
  7.5% vs. 13.9%; P=0.05 39.1 vs. 39.0 wk; P=0.43 10.8% vs. 15.5%; P=0.22 3325 vs. 3217 g; P=0.03 4.8% vs. 9.5%; P=0.09  
Ziaei 200727
Iran
n=727
Good
50 mg elemental iron daily starting at 20 wk of gestation Race: NR (Iran)
BMI: 24 kg/m2
Parity: 1.7
Score at 10 min: 9.9 vs. 9.8; P=NS     15% vs. 10%; P=0.035     0.8% vs. 1.7%; P=NS

BMI = body mass index; NR = not reported; NS = not significant; SES = socioeconomic status; WIC = Special Supplemental Nutrition Program for Women, Infants, and Children.
* P values in boldface show a significant difference.
Heme iron supplementation vs. no heme iron supplementation vs. placebo.

Appendix Table 3. Maternal Hematologic Outcomes*

Study,
Year, Country,
N,
Quality
Time Point Iron Supplement Dose, Formulation, and Initiation Risk Factors Reported Supplementation vs. Control
HB SF MCV Iron Deficiency (SF <12 µg/L) Anemia (HB <110 g/L) Iron Deficiency Anemia (HB <110 g/L and SF <12 µg/L)
Third trimester
Siega-Riz 200632
United States
n=429
Fair
26-29 wk (end of RCT phase) 30 mg elemental iron daily starting at <20 wk of gestation Race: Black 58%-65%, White 31%-37%
Single: 75%
Parity ≥2: 44% vs. 41%
SES: 100% eligible for WIC
114 vs. 114 g/L; P=0.81 49.4 vs. 45.6 pmol/L; P=0.48   53% vs. 65%; P=0.08 21% vs. 19%; P=0.65 10% vs. 15%; P=0.23
Cogswell 200329
United States
n=275
Fair
28 wk (end of RCT phase) 30 mg elemental iron daily starting at <20 wk of gestation Race: White 56%-57%, black 24%-26%, Hispanic 16%-17%
Parity ≥2: 31% vs. 24%
High school education or less: 73%-76%
SES: 100% eligible for WIC
117 vs. 116 g/L; P=0.499 38.9 vs. 38.3 wk; P=0.05 90.8 vs. 90.3 fL; P=0.443 56.4% vs. 65.1%; P=0.214 19.8% vs. 26.7%; P=0.251 12.7% vs. 20.9%; P=0.123
Falahi 201130
Iran
n=148
Fair
28 wk 60 mg elemental iron daily starting at <20 wk of gestation Race: NR (Iran)
BMI: 24-25 kg/m2
          1.4% vs. 3.8%; P<0.05
Ziaei 200727
Tehran, Iran n=727
Good
Third trimester 50 mg elemental iron daily starting at 20 wk of gestation Race: NR (Iran)
BMI: 24 kg/m2
Parity: 1.7
138 vs. 125 g/L; P<0.001          
Barton 199435
Ireland
n=97
Fair
36 wk 120 mg elemental iron daily starting at 14 wk of gestation Race: NR (Ireland)
Nulliparous: 45%-47%
135 vs. 126 g/L; P=0.043 (adjusted for smoking, P=0.25) 73.3 vs. 28.8 pmol/L; P=0.04        
Eskeland 199733
Norway
n=90
Fair
38 wk 27 mg elemental iron daily starting at 20 wk of gestation Race: NR (Norway)
BMI: 22-23 kg/m2
Parity ≥2: 0%-10%
Single: 3%-17%
Low education: 3%-10%
      29% vs. 52% vs. 85%; P<0.001 for A vs. C and P<0.05 for B vs. C    
At term
Meier 200331
United States
n=111
Fair
Delivery, 36-40 wk, stratified by age groups 60 mg elemental iron daily starting at first prenatal visit Race: NR (Wisconsin)
Private group practice
Adolescents 122 vs. 115 g/L; P=0.024
Adults 121 vs. 117 g/L; P=0.135
Adolescents 27.0 vs. 13.9 pmol/L; P=0.010
Adults 29.0 vs. 17.1 pmol/L; P=0.027
      Adolescents 5% vs. 29%; P=0.14
Adults 10.5% vs. 22.2%; P=0.26
Romslo 198336
Norway
n=45
Fair
37-40 wk 200 mg elemental iron daily starting within 10 wk of gestation Race: NR (Norway) 126 vs. 113 g/L; P=NR 53.9 vs. 13.5 pmol/L; P=NR   0% vs. 65.2%; P=0.02    
Barton 199435
Ireland
n=97
Fair
40 wk 120 mg elemental iron daily starting at 14 wk of gestation Race: NR (Ireland)
Nulliparous: 45%-47%
137 vs. 120 g/L; P<0.001       "No patients were withdrawn from the study due to anemia"  
Chan 200928
Hong Kong n=1164
Fair
Delivery 60 mg elemental iron daily starting at <16 wk of gestation Race: NR (Hong Kong)
Parity ≥2: 0.50% vs. 0.18%
BMI: 20.8 vs. 21.0 kg/m2
122 vs. 118 g/L; P<0.001 67.4 vs. 56.0 pmol/L; P<0.003        
Falahi 201130
Khorramabad City, Iran n=148
Fair
Delivery 60 mg elemental iron daily starting at <20 wk of gestation Race: NR (Iran)
BMI: 24-25 kg/m2
123 vs. 121 g/L; P=NS 63.1 vs. 49.7 pmol/L; P=NS   9.5% vs. 28.2%; P<0.05   0% vs. 0%; P=NS
Makrides 200325
Australia n=430
Good
Delivery 20 mg elemental iron daily starting at 20 wk of gestation Race: White 95%, Aboriginal 0.9%-3.3%, Asian 1.4%-2.3%
Multiparous: 52%-53%
BMI: 26 kg/m2
Highest level of education: year <10: 12%-15%, year 11: 27%- 28%, year 12: 28%-33%, trade certificate or diploma: 5%-8%, tertiary degree: 21%
127 vs. 120 g/L; RR, 6.9 (95% CI, 4.4 to 9.3) 47.2 vs. 31.5 pmol/L; RR, 7.1 (CI, 4 to 10.2)   35% vs. 58%; RR, 0.60 (CI, 0.48 to 0.76) 7% vs. 16%; RR, 0.45 (CI, 0.25 to 0.82) 3% vs. 11%; RR, 0.28 (CI, 0.12 to 0.68)
Milman 199434
Denmark n=120
Fair
Term 66 mg elemental iron daily starting at 14-16 wk of gestation Race: NR (Denmark) 127 vs. 116 g/L; P<0.0001 49.4 vs. 31.5
pmol/L;
P<0.0001
      0% vs. 17.5%; P=0.03
Ziaei 200826)
Iran (location NR)
n=205
Good
Delivery 50 mg elemental iron daily starting at 20 wk of gestation Race: NR (Iran)
BMI: 24 kg/m2
Parity: 1.6-1.7
Educational level: primary school: 7%-11%, high school: 77%-83%, university: 10%-12%
139 vs. 128 g/L; P<0.0001 58.9 vs. 42.9 pmol/L; P<0.0001        
Postpartum
Eskeland 199733
Norway
n=90
Fair
1 wk postpartum 27 mg elemental iron daily starting at 20 wk of gestation Race: NR (Norway)
BMI: 22-23 kg/m2
Parity ≥2: 0%-10%
Single: 3%-17%
Low education: 3%-10%
        11.5% vs. 20.7%; P=0.25  
Eskeland 199733
Norway
n=90
Fair
6-10 wk postpartum 27 mg elemental iron daily starting at 20 wk of gestation Race: NR (Norway)
BMI: 22-23 kg/m2
Parity ≥2: 0%-10%
Single: 3%-17%
Low education: 3%-10%
      8% vs. 27% vs. 52%; P<0.01 for A vs. C, P=NS for others§    
Eskeland 199733
Norway
n=90
Fair
24 wk postpartum 27 mg elemental iron daily starting at 20 wk of gestation Race: NR (Norway)
BMI: 22-23 kg/m2
Parity ≥2: 0%-10%
Single: 3%-17%
Low education: 3%-10%
      4% vs. 17% vs. 51%; P<0.001 for A vs. C and P<0.05 for B vs. C§    
Makrides 200325
Australia n=430
Good
6 mo postpartum 20 mg elemental iron daily starting at 20 wk of gestation Race: White 95%, Aboriginal 0.9%-3.3%, Asian 1.4%-2.3%
Multiparous: 52%-53%
BMI: 26 kg/m2
Highest level of education: year <10: 12%-15%, year 11: 27%- 28%, year 12: 28%-33%, trade certificate or diploma: 5%-8%, tertiary degree: 21%
135 vs. 134 g/L; RR, 1.6 (CI,−0.1 to 3.3) 76.4 vs. 58.4 pmol/L; RR, 7.9 (CI, 3.5 to 12.3)   16% vs. 29%; RR, 0.57 (CI, 0.38 to 0.84) 3.7% vs. 4.5%; RR, 0.82 (CI, 0.30 to 2.21) 2.6% vs. 1.7%; RR, 1.55 (CI, 0.38 to 6.40)
Ziaei 200826
Iran (location NR)
n=205
Good
6 wk postpartum 50 mg elemental iron daily starting at 20 wk of gestation Race: NR (Iran)
BMI: 24 kg/m2
Parity: 1.6-1.7
Educational level: primary school: 7%-11%, high school: 77%-83%, university: 10%-12%
133 vs. 126 g/L; P<0.0001 48.8 vs. 41.6 pmol/L; P<0.0001        

BMI = body mass index; HB = hemoglobin; MCV = mean corpuscular volume; NR = not reported; NS = not significant; RCT = randomized, controlled trial; RR = risk ratio; SES = socioeconomic status; SF = serum ferritin; WIC = Special Supplemental Nutrition Program for Women, Infants, and Children.
* P values and RRs in boldface show a significant difference.
Iron deficiency defined as SF <20 μg/L.
Iron deficiency anemia defined as HB <110 g/L and SF <20 μg/L.
§ Heme iron supplementation (A) vs. no heme iron supplementation (B) vs. placebo (C).

Appendix Table 4. Maternal Adverse Events

Study, Year, Country,
N,
Quality
Iron Supplement Dose, Formulation, and Initiation Risk Factors Reported Supplementation vs. Control
Gestational Diabetes Pregnancy-Induced
Hypertension
GI Events Other
Barton 199435
Ireland n=97
Fair
120 mg elemental iron daily starting at 14 wk of gestation Race: NR (Ireland)
Nulliparous: 45%-47%
  Hypertensive disorder: 7.5% vs. 9.0%; P=0.78   Antepartum hemorrhage: 5.7% vs. 4.5%; P=0.81
Chan 200928
Hong Kong n=1164
Fair
60 mg elemental iron daily starting at <16 wk of gestation Race: NR (Hong Kong)
Parity ≥2: 0.50% vs. 0.18%
BMI: 20.8 vs. 21.0 kg/m2
At 28 wk of gestation: 10% vs. 10%; OR, 1.04 (95% CI, 0.7 to 1.53)     Nonadherence: 46% overall; P=NS
Cogswell 200329
United States n=275
Fair
30 mg elemental iron daily starting at <20 wk of gestation Race: white 56%-57%, black 24%-26%, Hispanic 16%-17%
Parity ≥2: 31% vs. 24%
High school education or less: 73%-76%
SES: 100% eligible for WIC
      Nonadherence at wk 28: 36.6% vs. 34.8%; P=NS
Side effects reported at >1 visit from enrollment to wk 28: 24.6% vs. 18.5%; P=NS
Eskeland 199733
Norway n=90
Fair
27 mg elemental iron daily starting at 20 wk of gestation Race: NR (Norway)
BMI: 22-23 kg/m2
Parity ≥2: 0%-10%
Single: 3%-17%
Low education: 3%-10%
      No difference in fatigue or other side effects; P=NS
Nonadherence: 19% (combined 2 iron groups) vs. 18%; P=NS
Falahi 201130
Iran
n=148
Fair
60 mg elemental iron daily starting at <20 wk of gestation Race: NR (Iran)
BMI: 24-25 kg/m2
  1.4% (1 case) vs. 0%; P=NS    
Makrides 200325
Australia n=430
Good
20 mg elemental iron daily starting at 20 wk of gestation Race: white 95%, Aboriginal 0.9%-3.3%, Asian 1.4%-2.3%
Multiparous: 52%-53%
BMI: 26 kg/m2
Highest level of education: year <10: 12%-15%, year 11: 27%- 28%, year 12: 28%-33%, trade certificate or diploma: 5%-8%, tertiary degree: 21%
    At 36 wk of gestation:
Nausea: 29% vs. 28%; RR, 1.04 (CI, 0.76 to 1.42)
Stomach pain: 35% vs. 30%; RR, 1.19 (CI, 0.89 to 1.58)
Heartburn: 68% vs. 69%; RR, 0.99 (CI, 0.86 to 1.13)
Vomiting: 12% vs. 13%; RR, 0.89 (CI, 0.53 to 1.50)
Rash: 7.5% vs. 0.2%; RR, 1.21 (CI, 0.58 to 2.51)
Bowel movement ≤3 times/wk: 4% vs. 1.6%; RR, 2.56 (CI, 0.69 to 9.51)
Nonadherence: 14% vs. 15%; P=NS
Meier 200331
United States n=111
Fair
60 mg elemental iron daily starting at first prenatal visit Race: NR (Wisconsin)
Private group practice
    Adolescents:
Nausea: 53% vs. 65%; P=NS
Vomiting: 41% vs. 41%; P=NS
Constipation: 29% vs. 12%; P=NS
Diarrhea: 13% vs. 17%; P=NS
Adults:
Nausea: 63% vs. 53%; P=NS
Vomiting: 35% vs. 21%; P=NS
Constipation: 24% vs. 28%; P=NS
Diarrhea: 14% vs. 24%; P=NS
Nonadherence: Adolescents: 4.5% vs. 12.6%; P=0.320
Adults: 2.2% vs. 16.1%; P=0.036
Romslo 198336
Norway n=45
Fair
200 mg elemental iron daily starting within 10 wk of gestation Race: NR (Norway)     "None of the women complained of discomfort that could be attributed to the medication" Nonadherence: 45% overall; P=NS
Siega-Riz 200632
United States n=429
Fair
30 mg elemental iron daily starting at <20 wk of gestation Race: black 58%-65%, white 31%-37%
Single: 75%
Parity ≥2: 44% vs. 41%
SES: 100% eligible for WIC
      Nonadherence: 34% vs. 37%; P=0.27
Ziaei 200727
Iran
n=727
Good
50 mg elemental iron daily starting at 20 wk of gestation Race: NR (Iran)
BMI: 24 kg/m2
Parity: 1.7
  10 (2.7%) vs. 3 (0.8%); P=0.05    

BMI = body mass index; GI = gastrointestinal; NR = not reported; NS = not significant; OR = odds ratio; RR = risk ratio; SES = socioeconomic status; WIC = Special Supplemental Nutrition Program for Women, Infants, and Children.

Current as of: March 2015

Internet Citation: Evidence Summary: Iron Deficiency Anemia in Pregnant Women: Screening and Supplementation. U.S. Preventive Services Task Force. March 2016.
https://www.uspreventiveservicestaskforce.org/Page/Document/evidence-summary22/iron-deficiency-anemia-in-pregnant-women-screening-and-supplementation

USPSTF Program Office   5600 Fishers Lane, Mail Stop 06E53A, Rockville, MD 20857