Importance: In 2015, the US Preventive Services Task Force (USPSTF) found insufficient evidence to assess the balance of benefits and harms of routine screening and supplementation for iron deficiency anemia during pregnancy.

Objective: To update the 2015 review on screening for iron deficiency anemia, in addition to iron deficiency during pregnancy, to inform the USPSTF.

Data Sources: Ovid MEDLINE and Cochrane databases through May 24, 2023; surveillance through May 24, 2024.

Study Selection: Randomized clinical trials of iron supplementation, screening effectiveness, treatment, and harms; observational studies of screening.

Data Extraction and Synthesis: Dual review of abstracts, full-text articles, study quality, and data abstraction. Data were pooled using a random-effects model.

Main Outcomes and Measures: Maternal and infant clinical outcomes, hematologic indices, and harms.

Results: Seventeen trials (N = 24,023) on maternal iron supplementation were included. Iron supplementation was associated with decreased risk of maternal iron deficiency anemia at term (4 trials, n = 2230; 8.6% vs 19.8%; relative risk, 0.40 [95% CI, 0.26-0.61]; I² = 20.5%) and maternal iron deficiency at term (6 trials, n = 2361; 46% vs 70%; relative risk, 0.47 [95% CI, 0.33-0.67]; I² = 81.9%) compared with placebo or no iron supplement. There were no statistically significant differences in maternal quality of life, rates of gestational diabetes, maternal hemorrhage, hypertensive disorders of pregnancy, cesarean delivery, preterm birth, infant low birth weight, or infants small for gestational age for maternal iron supplementation compared with placebo or no supplementation. Harms of iron supplementation included transient gastrointestinal adverse effects. No studies evaluated the benefits or harms of screening for iron deficiency or iron deficiency anemia during pregnancy. Data on the association between iron status and health outcomes, such as hypertensive disorders of pregnancy and preterm birth, were very limited.

Conclusions and Relevance: Routine prenatal iron supplementation reduces the incidence of iron deficiency and iron deficiency anemia during pregnancy, but evidence on health outcomes is limited or indicates no benefit. No studies addressed screening for iron deficiency or iron deficiency anemia during pregnancy. Research is needed to understand the association between changes in maternal iron status measures and health outcomes.

Iron deficiency is the most common pathologic cause of anemia during pregnancy, due in part to higher maternal iron needs and physiologic changes during pregnancy.^1-3 In the US, the overall prevalence of iron deficiency in pregnancy is nearly 18%, with a 5% prevalence of iron deficiency anemia,³ although these may be underestimates due to changing diagnostic cutoffs.^4,5 Disparities in prevalence of iron deficiency anemia and iron deficiency have been reported, with higher prevalence among non-Hispanic Black and Mexican American individuals³ and those at lower income levels.⁶

Given the high prevalence, screening for iron deficiency and iron deficiency anemia may lead to earlier identification and treatment and routine supplementation could treat underlying iron deficiency and iron deficiency anemia, potentially preventing negative health outcomes. However, evidence on the relationship between iron status and perinatal health outcomes is limited. Although older observational data report associations between various measures of iron status and negative perinatal outcomes in women and infants,^7-10 rigorous trial evidence has been inconsistent.^11-13

In 2015, the US Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to assess the balance of benefits and harms of screening for iron deficiency anemia in pregnant women (I statement).¹⁴ There was also inadequate evidence on treatment of iron deficiency anemia during pregnancy owing to lack of generalizability to US clinical settings in treatment studies, due to differential nutritional status or hemoparasite burden.¹⁵ The USPSTF also concluded that the evidence was insufficient to assess the balance of benefits and harms of routine iron supplementation for pregnant women (I statement). This systematic review was conducted to update the 2015 review on this topic^11,16 and inform an updated USPSTF recommendation, with an expanded scope to evaluate the effect of iron supplementation and screening on iron deficiency without anemia.

Scope of the Review

Detailed methods and evidence tables with additional study details are available in the full evidence report.¹⁷ Figure 1 and Figure 2 show the analytic frameworks and key questions that guided the review. This review was based on 2 separate analytic frameworks on the effectiveness of routine preventive iron supplementation during pregnancy and the effectiveness of screening for iron deficiency and iron deficiency anemia during pregnancy.

Data Sources and Searches

Searches included Ovid MEDLINE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials from June 1, 2014, to May 24, 2023 (for iron deficiency anemia) and from database inception to May 3, 2024 (for iron deficiency without anemia). For iron deficiency anemia, studies from the prior USPSTF review were included. Reference lists of relevant articles supplemented the searches. Surveillance was last conducted on May 24, 2024, and identified no studies eligible for inclusion.

Study Selection

Two investigators independently reviewed English-language titles, abstracts, and full-text articles for inclusion using predefined criteria (eMethods 1 in the JAMA Supplement).

The population included pregnant adolescents and adults asymptomatic for iron deficiency or iron deficiency anemia. For supplementation, the population was those without known iron deficiency or iron deficiency anemia at study entry. For screening, the treated population was those found to have screen-detected iron deficiency or iron deficiency anemia. Studies of nonpregnant individuals and those with known nutritional deficiencies or symptoms of iron deficiency or iron deficiency anemia were excluded. Nongendered terms (eg, person, individual) were used to increase inclusivity except where the data were specified as women or females, and the term “pregnant person” was used to characterize the study population that included pregnant women and other individuals capable of pregnancy.

For supplementation, interventions were oral iron supplementation or iron-fortified foods compared with placebo or no supplementation. Mean baseline gestational age at enrollment was used to estimate timing of dose initiation. Due to the availability of good- and fair-quality randomized clinical trials (RCTs) of supplementation, observational studies were only included for the association questions. Eligible maternal outcomes were health outcomes (eg, mortality, quality of life, preeclampsia, postpartum hemorrhage, postpartum depression, and cesarean delivery rates) and hematologic outcomes (eg, incidence of iron deficiency or iron deficiency anemia, hematologic indices). Infant outcomes were health outcomes (eg, perinatal mortality, respiratory distress, neonatal intensive care unit admission, low birth weight, small for gestational age, and preterm delivery) and hematologic outcomes. Adverse effects included clinical harms, harms leading to discontinuation, and accidental overdose. Timing of maternal outcomes was classified as during pregnancy, at term, and postpartum; infant outcomes were limited to the first year of life.

A question on the association between a change in maternal iron status and changes in health outcomes was included in both the screening (key question [KQ] 5) and supplementation (KQ3) frameworks. To be eligible for inclusion, studies had to examine the association between a change in maternal iron deficiency or iron deficiency anemia resulting from treatment or supplementation and improved health outcomes.

For the screening framework, studies compared screening with no screening or treatment with no treatment for screen-detected iron deficiency or iron deficiency anemia. Eligible interventions were routine blood tests (eg, complete blood cell count) and supplementation with oral or intravenous iron or iron-fortified foods. Eligible study designs included RCTs or controlled observational studies as well as large uncontrolled observational studies on harms. Supplementation outcomes also applied to the screening framework, with additional screening for specific harms such as overdiagnosis, anxiety, and labeling.

Inclusion was restricted to studies conducted in primary care or prenatal settings and in countries categorized in 2020 as high or very high on the United Nations Human Development Index (HDI)¹⁹ to enhance applicability to US primary care/prenatal settings. Trial from China were included for this update because of reclassification from a medium to a high HDI rating in 2011/2012.^20,21

Data Extraction and Quality Rating

A single investigator abstracted details from each study including study design, patient population, setting, interventions, analysis, follow- up, and results. A second investigator reviewed data for accuracy. Two independent investigators assessed the quality of each study as good, fair, or poor using predefined criteria developed by the USPSTF (eMethods 2 in the JAMA Supplement).¹⁸ In accordance with the USPSTF Procedure Manual,¹⁸ poor quality studies were excluded.

Data Synthesis

Meta-analyses using the DerSimonian-Laird random-effects model (STATA version 14.2 [StataCorp]) were conducted for outcomes and comparisons for which there were multiple studies comparable enough to provide a meaningful combined estimate.²² Stratified analyses were conducted to assess the potential variation across studies by country HDI rating (defined as very high HDI vs high HDI) and supplementation dosing based on elemental iron dose (defined as high if ≥60 mg and low if <60 mg). Hematologic values were pooled separately at term and third trimester time points; postpartum time points were not pooled due to variable and less frequent reporting. For intermediate outcomes, data were pooled for risk of iron deficiency or iron deficiency anemia, which were considered more informative than changes in individual hematologic indices such as ferritin or hemoglobin level.

Two independent reviewers assessed the aggregate internal validity (quality) for each KQ using methods developed by the USPSTF¹⁸ based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence.¹⁸ Disagreements were resolved through consensus.

Across all KQs, 18 studies (reported in 28 publications^23-50) of maternal iron supplementation (17 RCTs [N = 24,023] and 1 observational study²⁷ [N = 20,690]) were included (Figure 3). The observational study evaluated the association between improvement in iron indices and health outcomes and was relevant for both analytic frameworks. No other study addressed KQs on screening for iron deficiency or iron deficiency anemia. Twelve RCTs^{23,24,26,28,29,34,36,37,41,43,48,49} addressing iron supplementation were carried forward from the prior USPSTF report.¹¹ Five RCTs^{30,32,40,45,46} and the observational study²⁷ were added for this update.

Benefits of Supplementation

Key Question 1. What are the benefits of routine iron supplementation during pregnancy on maternal and infant health outcomes?

Sixteen trials (in 26 publications) compared the effects of routine preventive iron supplementation vs no supplementation during pregnancy. Twelve trials (in 14 publications)^{23,24,26,28,29,34,36-38,41,43,47-49} were carried forward from the prior review.¹¹ Four additional trials^{25,31-33,35,40,42,44-46} and 2 new secondary publications^39,50 of older trials^34,37 were identified for this update. Three studies were conducted in the US,^26,36,43 3 in rural China,^32,45,46 and 4 in Iran;^29,40,48,49 the others were conducted in Hong Kong,²⁴ Australia,³⁴ or Europe.^23,28,37,41

Sample sizes ranged from 52 to 12,513 participants (total n = 23,844). Four studies had more than 1000 participants; 3 were added for this update, had the largest sample sizes, and were conducted in rural China (n = 12,513,³² 3929,⁴⁵ and 2371⁴⁶). Most studies included pregnant individuals at a average risk for anemia and excluded those with baseline hemoglobin level below 8 g/dL to 11 g/dL, preexisting anemia, or related chronic conditions.^{23,24,26,28,32,34,36,40,43,46,48,49} Mean baseline hemoglobin levels ranged from 11.9 g/dL to 14.3 g/dL. Seven studies reported providing treatment if hematologic indices dropped too low in the supplementation group during the course of the study.^{24,28,34,36,40,48,49} Studies enrolled participants aged 20 to 30 years; 2 studies also included adolescents.^36,43 In 1 US study, 58% to 65% of participants were Black;⁴³ in another US study, 16% to 17% of participants were Hispanic, 24% to 25% non-Hispanic Black, and 56% to 57% non-Hispanic White.⁴³ Both of these studies restricted enrollment to individuals eligible for or participating in Special Supplemental Nutrition Program for Women, Infants, and Children services. Race, ethnicity, and socioeconomic status were not reported in the third US-based study, which was set in private group practice in Wisconsin.³⁶ No study stratified results according to population characteristics.

In all studies, supplementation was initiated at the first prenatal visit (up to 20 weeks’ gestation) and continued through delivery; mean gestational age at enrollment ranged from 11 to 16 weeks in studies that reported this information. In 2 US studies, all participants in the placebo group received supplementation at 26 to 29 weeks’ gestation.^26,43 Outcomes were measured during the third trimester, at delivery, or included follow-up into the postpartum period (1 day to 6 months postpartum); 1 study included health-related quality of life follow-up to 4 years.⁵⁰ Supplement dosing ranged from 20 to 200 mg of elemental iron daily. Intervention groups in most studies received 30 to 60 mg of elemental iron daily; 1 study used 20 mg,³⁴ and 2 smaller studies used higher doses of 120 mg²³ or 200 mg.⁴¹ Nonadherence, usually based on pill counts, ranged from 4.5% to 68%.^{24,26,28,32,34,36,41,43,45,46}

Four studies were rated good quality^32,34,48,49 and 12 studies were rated fair quality^{23,24,26,28,29,36,37,40,41,43,45,46} due to unclear randomization and allocation concealment methods; unclear masking of outcome assessors; high or unclear attrition or differential attrition; and inadequate randomization methods.

Table 1 reports the results of meta-analyses, including analyses stratified by country and dose; forest plots for the primary meta-analyses are provided in eFigures 1-8 in the JAMA Supplement.

Maternal Clinical Outcomes

Routine iron supplementation was not associated with reduced risk of hypertensive disorders of pregnancy (eg, pregnancy-induced hypertension,^29,32,40 hypertensive disorder, or not defined^23,49) compared with placebo, although the estimate was imprecise (5 trials; n = 13,610; 4.7% vs 3.1% [all studies pooled, weighted rates]; relative risk [RR], 1.24 [95% CI, 0.75-2.06]; I² = 48%) (eFigure 1 in the JAMA Supplement).^{23,29,32,40,49} One trial found that supplementation was not associated with reduced risk of preeclampsia vs placebo but also had an imprecise estimate (3.9% vs 2.7%; RR, 1.45 [95% CI, 0.67-3.16]). Routine iron supplementation and placebo were associated with similar risk of cesarean delivery vs placebo (8 studies; n = 4919; 42.8% vs 41.5%; RR, 1.01 [95% CI, 0.90-1.14]; I² = 42.7%) (eFigure 2 in the JAMA Supplement).^{23,24,34,36,40,46,48,49} Clinical indications for cesarean delivery were not reported in any study. Findings were similar when analyses were stratified by country HDI category and dose.

One trial (n = 430) found no statistically significant differences between routine iron supplementation during pregnancy vs placebo or no supplement on quality of life based on the 36-Item Short Form Health Survey at 36 weeks’ gestation or at 6 weeks, 6 months, or 4 years postpartum.^34,50 There were also no statistically significant differences in risk of gestational diabetes (2 trials;^24,40 n = 2124) or risk of maternal hemorrhage (2 trials;^23,48 n = 341), although rates of hemorrhage were low (eTable 1 in the JAMA Supplement).

Maternal Hematologic Outcomes

Sixteen trials (n = 23,844) reported maternal incidence of iron deficiency or iron deficiency anemia (Table 1; eTable 2 [third trimester], eTable 3 [term], and eTable 4 [postpartum] in the JAMA Supplement).^{23-26,28,29,31-49} Routine iron supplementation during pregnancy was associated with a statistically significant decreased risk of maternal iron deficiency anemia at term (4 trials; n = 2230; 8.6% vs 19.8%; RR, 0.40 [95% CI, 0.26-0.61]; I² = 20.5%; absolute risk difference [ARD], −9.59% [95% CI, −16.2% to −2.98%]) (eFigure 3 in the JAMA Supplement); maternal iron deficiency at term (6 trials; n = 2361; 46% vs 70%; RR, 0.47 [95% CI, 0.33-0.67]; I² = 81.9%; ARD, −34.25% [95% CI, −46.49% to −22.01%]) (eFigure 4 in the JAMA Supplement); and anemia at term (4 trials; n = 2261; 10.9% vs 22.5%; RR, 0.43 [95% CI, 0.26-0.72]; I² = 43.7%; ARD, −11.73% [95% CI, −14.87% to −8.60%]) (eFigure 5 in the JAMA Supplement) compared with placebo or no supplementation. Findings were similar for third trimester outcomes. For iron deficiency and iron deficiency anemia, stratified analysis by country HDI category and dose resulted in similar findings.

Infant Clinical Outcomes

Eleven trials (n = 20,435; 3 good quality^32,34,49 and 8 fair quality^{23,24,29,36,38,40,41,45}) reported infant birth outcomes including infant mortality, preterm delivery, small size for gestational age, and low birth weight (eTable 5 in the JAMA Supplement; summary of meta-analyses in Table 1).

Comparing maternal iron supplementation with placebo, there were no statistically significant differences in risk of preterm birth (5 trials;^{24,29,32,40,45} n = 16,827; 5.5% vs 6.0%; RR, 0.92 [95% CI, 0.81-1.04]; I² = 0.0%) (eFigure 6 in the JAMA Supplement); infants small for gestational age (4 trials;^24,40,45,49 n = 5386; 15.3% vs 15.2%; RR, 0.94 [95% CI, 0.67-1.31]; I² = 75.5%) (eFigure 7 in the JAMA Supplement); or infants with low birth weight (6 trials;^{23,29,32,34,36,45} n = 15,591; 2.7% vs 2.9%; RR, 0.95 [95% CI, 0.79-1.14]; I² = 0.0%) (eFigure 8 in the JAMA Supplement), although some imprecision in estimates was present. There was no statistically significant interaction between country HDI category or iron dose and effects of supplementation on infant outcomes (Table 1). There was statistical heterogeneity in the pooled estimate for small for gestational age. One small trial from Hong Kong found iron supplementation (60 mg) vs placebo associated with decreased risk of infant small for gestational age (3.6% vs −7.5%; RR, 0.48 [95% CI, 0.26-0.87]),²⁴ the 3 other trials from high HDI countries showed no statistically significant differences or favored placebo.^40,45,49 Infant mortality rates were not a prespecified outcome in any study, and event rates were low (<1% to 2%).

Infant Hematologic Outcomes

Two trials (n = 12,943) found no statistically significant differences between routine iron supplementation during pregnancy vs placebo in infant hematologic indices at 6 months or 1 year follow-up.^32,34

Harms of Supplementation

Key Question 2. What are the harms of routine iron supplementation during pregnancy?

Eleven trials (n = 22,536)^{24,26,28,32,34,36,40,41,43,45,46} included for KQ1 and 1 additional trial³⁰ addressed supplementation harms (eTable 6 in the JAMA Supplement). No trial reported any serious adverse events from iron supplementation, and infant harms were not reported in any study. One large (n = 12,513) trial conducted in rural China found elemental iron supplementation (30 mg) beginning in the second trimester associated with increased risk of gastrointestinal symptoms vs placebo (3.6% vs 2.3%; RR, 1.59 [95% CI, 1.28-1.97]).³² In contrast, no statistically significant differences in rates of gastrointestinal adverse effects (variably defined) between supplementation and placebo groups were reported in 5 other studies (n = 7053).^{30,34,36,45,46}

Nonadherence, a potential marker of intolerability, was similar between supplementation vs placebo in 10 trials (n = 21,397).^{24,26,28,32,34,36,41,43,45,46}

Change in Maternal Iron Status and Improvement in Newborn and Peripartum Outcomes

Key Question 3. In pregnant persons with iron deficiency, with or without anemia, what is the association between change in maternal iron status (including changes in ferritin or hemoglobin level) and improvement in newborn and peripartum outcomes in US relevant populations?

One fair-quality, US-based observational study (n = 20,690) added for this update compared the association between response to iron supplementation in pregnant persons with iron deficiency (with or without anemia) and risk of preeclampsia or preterm delivery.²⁷ Patients in a perinatal database were classified as anemic (n = 7416) or nonanemic (reference group; n = 13,274), with anemic patients further categorized by treatment group (treated or untreated anemic, n = 3402) and, among those treated, response to treatment (refractory anemic, n = 1319; or successfully treated, n = 2695). Dosing, timing, and duration of treatment or iron supplementation was not reported. Most participants identified as Black race (9%-24%) or Hispanic ethnicity (43%-63%). Methodologic limitations included unclear documentation of iron deficiency or use of supplementation and unclear classification and reporting of symptoms.

Successful response to treatment was defined as presenting to labor and delivery with normal hemoglobin level and reporting having taken iron supplementation; this was associated with reduced risk of preterm birth (adjusted odds ratio [OR], 0.59 [95% CI, 0.47- 0.72]) and preeclampsia (adjusted OR, 0.75 [95% CI, 0.6-0.91]) vs no anemia. Refractory or untreated anemia was associated with increased risk of preterm birth and preeclampsia (adjusted OR, 1.44 [95% CI, 1.16-1.76] and adjusted OR, 1.45 [95% CI, 1.26-1.67], respectively) vs no anemia. There were no differences between groups in composite neonatal morbidity.

Screening for Iron Deficiency and Iron Deficiency Anemia During Pregnancy

No studies addressed key questions on the effectiveness of screening on any maternal or infant health outcomes, including benefits or harms. Evidence on the association between change in maternal iron status and improvement in outcomes (KQ3) is addressed in the JAMA Supplement.

The findings of this evidence report are summarized in Table 2 and Table 3. Despite the inclusion of data from 5 additional RCTs of supplementation,^{30,32,40,45,46} conclusions were consistent with findings from the previous USPSTF review.¹¹ Specifically, iron supplementation decreases the risk of iron deficiency or iron deficiency anemia during pregnancy and at delivery, without evidence of improvement in maternal or infant clinical outcomes. As in the prior USPSTF review, no studies evaluated the benefits or harms of screening. Expanding the scope to assess the impact of iron supplementation or screening on iron deficiency alone or inclusion of trials from high HDI index countries (including rural China) did not affect the results.

There were no clear effects of prenatal iron supplementation on maternal clinical outcomes including hypertensive disorders of pregnancy, gestational diabetes, or cesarean delivery, but estimates were imprecise. Results were somewhat inconsistent for cesarean delivery, with 1 fair-quality, large trial²⁴ finding supplementation associated with reduced risk of cesarean delivery but 8 trials of varying sizes and similar dosing regimens finding no difference. However, effects on cesarean delivery are difficult to interpret due to lack of information on indications (eg, elective or urgent) and the lack of a clear mechanism by which iron deficiency or iron deficiency anemia would affect cesarean delivery. Some observational studies^51-53 not eligible for this review suggest that iron supplementation may increase the risk of gestational diabetes, but results are susceptible to residual confounding. Data on harms were limited, but no serious harms were reported.

Regarding infant health outcomes, iron supplementation was not associated with decreased rates of preterm delivery, low birth weight infants, or infants small for gestational age. Findings regarding infant outcomes were limited by relatively small numbers of trials (eg, 6 trials reporting preterm delivery, 3 trials reporting small for gestational age, and 6 trials for low birth weight) and imprecision. In addition, there was unexplained statistical heterogeneity in the pooled estimate for small for gestational age. There was insufficient evidence to assess the effect of prenatal iron supplementation on infant mortality due to low event rates.

As in the prior USPSTF review, maternal iron supplementation, compared with placebo or no supplements, was associated with improved hematologic indices or incidence of iron deficiency or iron deficiency anemia, but the clinical significance of these findings remains unclear. No study evaluated outcomes of screening vs no screening for iron deficiency or iron deficiency anemia in pregnant adults or adolescents. One study of supplementation added to this review provided insufficient evidence to evaluate the association between a change in maternal iron status and clinical outcomes, due to serious methodological limitations.²⁷

Studies included in this review focused on pregnant adults and adolescents at average risk for anemia and excluded those with very low hematologic indices at baseline or preexisting anemia or related chronic conditions. Therefore, results of this review may not apply to settings in which pregnant individuals have lower baseline hematologic indices or higher incidence of severe anemia. No study evaluated how outcomes of supplementation varied by population, including those defined by race or ethnicity. Observational studies suggest potential disparities in the incidence of iron deficiency and iron deficiency anemia by socioeconomic status and race or ethnicity, but data are difficult to interpret due to variation in practice guidelines and variability in diagnostic cutoffs by race or ethnicity and may be affected by access to health care services.

Limitations

This review had several limitations. First, non–English-language articles were excluded, which could result in language bias, although no non–English-language studies that would have met inclusion criteria were identified. Second, publication bias was not formally assessed with graphical or statistical methods⁵⁴ because of small numbers of studies and differences in study design, populations, and outcomes assessed. Third, some trials eligible for inclusion because of country categorization as high on the HDI (eg, Hong Kong, rural China, Iran) may have limited generalizability to the US due to differences in nutritional status, diet, resources, infrastructure, or other factors.^19,55,56 However, stratified analyses did not indicate subgroup differences based on HDI category (high vs very high). Fourth, due to anticipated statistical heterogeneity with regard to populations, setting, rates of iron deficiency or iron deficiency anemia, supplementation dose and timing, and other factors, the DerSimonian and Laird random-effects model was used to pool studies, which may result in overly narrow confidence intervals when heterogeneity is present, particularly when the number of studies is small.²² To evaluate statistical heterogeneity, subgroup analysis was performed to assess the sensitivity of results to variations across study characteristics, including country HDI rating and low and high supplementation dosing based on elemental iron doses. Results did not indicate statistically significant subgroup effects based on these characteristics. However, the utility of stratified analyses was limited by relatively small numbers of trials.

Routine prenatal iron supplementation reduces the incidence of iron deficiency and iron deficiency anemia during pregnancy, but evidence on health outcomes is limited or indicates no benefit. No studies addressed screening for iron deficiency or iron deficiency anemia during pregnancy. Research is needed to understand the association between changes in maternal iron status measures and health outcomes.

Source: This article was published online in JAMA on August 20, 2024 (JAMA. doi:10.1001/jama.2024.13546).

Conflict of Interest Disclosures: Dr DeLoughery reported serving as an editor for UpToDate. No other disclosures were reported.

Funding/Support: This research was funded under contract 75Q80120D00006, Task Order 75Q80121F32009, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We gratefully acknowledge the AHRQ Medical Officer (Sheena Harris, MD, MPH) and the USPSTF. The USPSTF members, expert consultants, peer reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 4 content experts (Jeanne Conry, MD, PhD [International Federation of Gynecology and Obstetrics and the Environmental Health Leadership Foundation]; Anjali Kaimal, MD, MAS [Division of Maternal-Fetal Medicine, Massachusetts General Hospital]; Robert Means, MD [East Tennessee State University]; Kimberly O’Brien, PhD [Cornell University]) and 3 federal partner reviewers from the National Institute on Minority Health and Health Disparities and the Office of Research on Women’s Health. Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

1. Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep. 1998;47(RR-3):1-29.
2. Institute of Medicine (US), Committee on the Prevention Detection and Management of Iron Deficiency Anemia Among US Children and Women of Childbearing Age. Iron Deficiency Anemia: Recommended Guidelines for the Prevention, Detection, and Management Among US Children and Women of Childbearing Age. National Academies Press; 1993.
3. Mei Z, Cogswell ME, Looker AC, 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(6):1312-1320. doi:10.3945/ajcn.110.007195
4. Auerbach M, Abernathy J, Juul S, Short V, Derman R. Prevalence of iron deficiency in first trimester, nonanemic pregnant women. J Matern Fetal Neonatal Med. 2021;34(6):1002-1005. doi:10.1080/14767058.2019.1619690
5. Teichman J, Nisenbaum R, Lausman A, Sholzberg M. Suboptimal iron deficiency screening in pregnancy and the impact of socioeconomic status in a high-resource setting. Blood Adv. 2021;5(22):4666-4673. doi:10.1182/bloodadvances.2021004352
6. Bodnar LM, Cogswell ME, Scanlon KS. Low income postpartum women are at risk of iron deficiency. J Nutr. 2002;132(8):2298-2302. doi:10.1093/jn/132.8.2298
7. 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(5):985-988. doi:10.1093/ajcn/55.5.985
8. Klebanoff MA, Shiono PH, Selby JV, Trachtenberg AI, Graubard BI. Anemia and spontaneous preterm birth. Am J Obstet Gynecol. 1991;164(1, pt 1):59-63. doi:10.1016/0002-9378(91)90626-3
9. 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(10):998-1006. doi:10.1093/oxfordjournals.aje.a009577
10. Scholl TO, Hediger ML. Anemia and iron-deficiency anemia: compilation of data on pregnancy outcome. Am J Clin Nutr. 1994;59(2) (suppl):492S-500S. doi:10.1093/ajcn/59.2.492S
11. McDonagh M, Cantor A, Bougatsos C, et al. Routine Iron Supplementation and Screening for Iron Deficiency Anemia in Pregnant Women: A Systematic Review to Update the US Preventive Services Task Force Recommendation. Agency for Healthcare Research and Quality; 2015. AHRQ report 13-05187-EF-2. https://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=medp&NEWS=N&AN=25927136
12. Peña-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;(4):CD004736. doi:10.1002/14651858.CD004736.pub3
13. Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2011;(10):CD003094. doi:10.1002/14651858.CD003094.pub3
14. Siu AL; US Preventive Services Task Force. Screening for iron deficiency anemia and iron supplementation in pregnant women to improve maternal health and birth outcomes: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;163(7):529-536. doi:10.7326/M15-1707
15. Kemper AR, Fan T, Grossman DC, Phipps MG. Gaps in evidence regarding iron deficiency anemia in pregnant women and young children: summary of US Preventive Services Task Force recommendations. Am J Clin Nutr. 2017;106(suppl 6):1555S-1558S. doi:10.3945/ajcn.117.155788
16. Cantor AG, Bougatsos C, Dana T, Blazina I, McDonagh M. Routine iron supplementation and screening for iron deficiency anemia in pregnancy: a systematic review for the US Preventive Services Task Force. Ann Intern Med. 2015;162(8):566-576. doi:10.7326/M14-2932
17. Cantor AG, Bougatsos C, Atchison C, DeLoughery T, Chou R. Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia in Pregnancy: A Systematic Review for the US Preventive Services Task Force. Evidence Synthesis No. 239. Agency for Healthcare Research and Quality; 2024. AHRQ publication 24-05313-EF-1.
18. US Preventive Services Task Force. US Preventive Services Task Force Procedure Manual. Updated May 2021. Accessed July 10, 2024. https://www.uspreventiveservicestaskforce.org/uspstf/about-uspstf/methods-and-processes/procedure-manual
19. United Nations Development Programme. Human Development Report 2020. Published 2020. Accessed July 19, 2024. https://hdr.undp.org/content/human-development-report-2020
20. United Nations Development Programme. National Human Development Report 2019: China. Published 2019. Accessed July 19, 2024. https://hdr.undp.org/system/files/documents/nhdrcnpdf.pdf
21. United Nations Development Programme. Human Development Index (HDI). Accessed July 19, 2024. https://hdr.undp.org/en/statistics/
22. Cornell JE, Mulrow CD, Localio R, et al. Random-effects meta-analysis of inconsistent effects: a time for change. Ann Intern Med. 2014;160(4):267-270. doi:10.7326/M13-2886
23. Barton DP, Joy MT, Lappin TR, et al. Maternal erythropoietin in singleton pregnancies: a randomized trial on the effect of oral hematinic supplementation. Am J Obstet Gynecol. 1994;170(3):896-901. doi:10.1016/S0002-9378(94)70305-1
24. Chan KKL, Chan BCP, Lam KF, Tam S, Lao TT. Iron supplement in pregnancy and development of gestational diabetes—a randomised placebo-controlled trial. BJOG. 2009;116(6):789-797. doi:10.1111/j.1471-0528.2008.02014.x
25. Chen S, Li N, Mei Z, et al. Micronutrient supplementation during pregnancy and the risk of pregnancy-induced hypertension: a randomized clinical trial. Clin Nutr. 2019;38(1):146-151. doi:10.1016/j.clnu.2018.01.029
26. 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(4):773-781. doi:10.1093/ajcn/78.4.773
27. Detlefs SE, Jochum MD, Salmanian B, McKinney JR, Aagaard KM. The impact of response to iron therapy on maternal and neonatal outcomes among pregnant women with anemia. Am J Obstet Gynecol MFM. 2022;4(2):100569. doi:10.1016/j.ajogmf.2022.100569
28. 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(9):822-828. doi:10.3109/00016349709024359
29. 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(3):213-217. doi:10.1177/156482651103200305
30. Jafarbegloo E, Ahmari Tehran H, Dadkhah Tehrani T. Gastrointestinal complications of ferrous sulfate in pregnant women: a randomized double-blind placebo-controlled trial. Iran Red Crescent Med J. 2015;17(8):e15001. doi:10.5812/ircmj.15001
31. Li Z, Mei Z, Zhang L, et al. Effects of prenatal micronutrient supplementation on spontaneous preterm birth: a double-blind randomized controlled trial in China. Am J Epidemiol. 2017;186(3):318-325. doi:10.1093/aje/kwx094
32. Liu JM, Mei Z, Ye R, Serdula MK, Ren A, Cogswell ME. Micronutrient supplementation and pregnancy outcomes: double-blind randomized controlled trial in China. JAMA Intern Med. 2013;173(4):276-282. doi:10.1001/jamainternmed.2013.1632
33. Liu Y, Li N, Mei Z, et al. Effects of prenatal micronutrients supplementation timing on pregnancy-induced hypertension: secondary analysis of a double-blind randomized controlled trial. Matern Child Nutr. 2021;17(3):e13157. doi:10.1111/mcn.13157
34. MakridesM, 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(1):145-153. doi:10.1093/ajcn/78.1.145
35. Mei Z, Serdula MK, Liu JM, et al. Iron-containing micronutrient supplementation of Chinese women with no or mild anemia during pregnancy improved iron status but did not affect perinatal anemia. J Nutr. 2014;144(6):943-948. doi:10.3945/jn.113.189894
36. 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(1):29-36. doi:10.3121/cmr.1.1.29
37. 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(6):471-476.
38. 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(3):200-204. doi:10.3109/ 00016349409023439
39. Milman N, Byg KE, Agger AO. Hemoglobin and erythrocyte indices during normal pregnancy and postpartum in 206 women with and without iron supplementation. Acta Obstet Gynecol Scand. 2000;79(2):89-98. doi:10.1034/j.1600-0412.2000. 079002089.x
40. Ouladsahebmadarek E, Sayyah-Melli M, Taghavi SAS, Seyedhejazie M. The effect of supplemental iron elimination on pregnancy outcome. Pak J Biol Sci. 2011;27(3):641-645.
41. 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(2):101-107. doi:10.1111/j.1471-0528.1983.tb08891.x
42. Serdula MK, Zhou Y, Li H, Liu JM, Mei Z. Prenatal iron containing supplements provided to Chinese women with no or mild anemia had no effect on hemoglobin concentration in post-partum women or their infants at 6 and 12 months of age. Eur J Clin Nutr. 2019;73(11):1473-1479. doi:10.1038/s41430-018-0365-x
43. 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(2):512-519. doi:10.1016/j.ajog.2005.08.011
44. Wang L, Mei Z, Li H, Zhang Y, Liu J, Serdula MK. Modifying effects of maternal Hb concentration on infant birth weight in women receiving prenatal iron-containing supplements: a randomised controlled trial. Br J Nutr. 2016;115(4):644-649. doi: 10.1017/S0007114515004870
45. Zeng L, Dibley MJ, Cheng Y, et al. Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: double blind cluster randomised controlled trial. BMJ. 2008;337:a2001. doi:10.1136/bmj.a2001
46. Zhao G, Xu G, Zhou M, et al. Prenatal iron supplementation reduces maternal anemia, iron deficiency, and iron deficiency anemia in a randomized clinical trial in rural China, but iron deficiency remains widespread in mothers and neonates. J Nutr. 2015;145(8):1916-1923. doi:10.3945/jn.114.208678
47. Zhou SJ, Gibson RA, MakridesM. 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(4):438-440. doi:10.1016/j. jpeds.2007.06.001
48. Ziaei S, Mehrnia M, Faghihzadeh S. Iron status markers in nonanemic pregnant women with and without iron supplementation. Int J Gynaecol Obstet. 2008;100(2):130-132. doi:10.1016/j.ijgo.2007.07.027
49. 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. [Published correction appears in BJOG. 2007;114(10):1311]. BJOG. 2007;114(6):684-688. doi:10.1111/j.1471-0528.2007.01325. x
50. Zhou SJ, Gibson RA, Crowther CA, Baghurst P, Makrides M. Effect of iron supplementation during pregnancy on the intelligence quotient and behavior of children at 4 y of age: long-term follow-up of a randomized controlled trial. Am J Clin Nutr. 2006;83(5):1112-1117. doi:10.1093/ajcn/83.5.1112
51. Petry CJ, Ong KK, Hughes IA, Dunger DB. Associations between maternal iron supplementation in pregnancy and changes in offspring size at birth reflect those of multiple micronutrient supplementation. Nutrients. 2021;13(7):2480. doi:10.3390/nu13072480
52. Zhang Y, Xu S, Zhong C, et al. Periconceptional iron supplementation and risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Res Clin Pract. 2021;176:108853. doi:10.1016/j.diabres.2021.108853
53. Martínez-Galiano JM, Amezcua-Prieto C, Cano-Ibañez N, Salcedo-Bellido I, Bueno-Cavanillas A, Delgado-Rodriguez M. Maternal iron intake during pregnancy and the risk of small for gestational age. Matern Child Nutr. 2019;15(3):e12814. doi:10.1111/mcn.12814
54. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. doi:10.1136/bmj.d4002
55. Mansukhani R, Shakur-Still H, Chaudhri R, et al; WOMAN-2 Trial Collaborators. Maternal anaemia and the risk of postpartum haemorrhage: a cohort analysis of data from the WOMAN-2 trial. Lancet Glob Health. 2023;11(8):e1249-e1259. doi:10.1016/S2214-109X(23)00245-0
56. Omotayo MO, Abioye AI, Kuyebi M, Eke AC. Prenatal anemia and postpartum hemorrhage risk: a systematic review and meta-analysis. J Obstet Gynaecol Res. 2021;47(8):2565-2576. doi:10.1111/ jog.14834

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions (KQs) that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. A dashed line depicts a health outcome that follows an intermediate outcome. For additional information, see the USPSTF Procedure Manual.¹⁸

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions (KQs) that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. A dashed line depicts a health outcome that follows an intermediate outcome. For additional information, see the USPSTF Procedure Manual.¹⁸

^a The sum of the number of studies per key question (KQ) exceeds the total number of studies because some studies were applicable to multiple KQs.
^b KQ3 in the routine iron supplementation framework and KQ5 in the screening for iron deficiency and iron deficiency anemia framework are the same KQ and therefore cover the same evidence.

Abbreviations: ARD, absolute risk difference; HDI, Human Development Index; NA, not applicable; RR, relative risk.
^a Statistically significant.

Abbreviations: ARD, absolute risk difference; HDI, Human Development Index; KQ, key question; LBW, low birth weight; NA, not available; OR, odds ratio; PIH, pregnancy-induced hypertension; RCT, randomized clinical trial; RR, relative risk; SF-36, 36-Item Short Form Health Survey.

Abbreviations: KQ, key question; NA, not applicable.
^a Same as KQ3 in the supplementation framework.