s12905 023 02291 6

Ali et al.
BMC Women’s Health (2023) 23:184 BMC Women’s Health

https://doi.org/10.1186/s12905-023-02291-6
RESEARCH Open Access
Role of iron in the reduction of anemia

among women of reproductive age
in low‑middle income countries: insights
from systematic review and meta‑analysis
Sumera Aziz Ali1*, Shama Razzaq2, Savera Aziz3, Ahreen Allana4, Arzina Aziz Ali4, Shahla Naeem5,
Nayab Khowaja6 and Fazal Ur Rehman4
Abstract
Background Iron deficiency anemia is a common public health issue among women of reproductive age (WRA)
because it can result in adverse maternal and birth outcomes. Although studies are undertaken to assess iron efficacy,
some gaps and limitations in the existing literature need to be addressed. To fill the gaps, we conducted a systematic
review and meta-analysis of randomized controlled trials (RCTs) assessing the role of iron in reducing anemia among
WRA in low-middle-income countries (LMICs).
Methods A comprehensive search strategy was used to search Medline through PubMed, Embase, and Science
Direct for RCTs published between 2000 and 2020. The primary outcome was the mean change in hemoglobin level.
We used standardized mean differences and their respective 95% CI to estimate the pooled effect. We used I2 statistics
and Egger’s test to assess heterogeneity and publication bias, respectively. This review was carried out in accordance
with revised guidelines based on the Preferred Reporting Items for Systematic Review and Meta-analysis.
Results The findings showed that iron therapy improved hemoglobin and ferritin levels, though the results varied
across studies. An overall pooled effect estimate for the role of iron therapy in improving the hemoglobin levels
among WRA was -0.71 (95% CI: -1.27 to -0.14) (p = 0.008). Likewise, the overall pooled effect estimate for the role of
iron therapy in improving the ferritin levels among WRA was -0.76 (95% CI: -1.56 to 0.04) (p = 0.04). The heterogene-
ity (I2) across included studies was found to be statistically significant for studies assessing hemoglobin (Q = 746.93,
I2 = 97.59%, p = 0.000) and ferritin level (Q = 659.95, I2 = 97.88%, p = 0.000).
Conclusion Iron therapy in any form may reduce anemia’s burden and improve hemoglobin and ferritin levels,
indicating improvement in iron-deficiency anemia. More evidence is required, however, to assess the morbidity
associated with iron consumption, such as side effects, work performance, economic outcomes, mental health, and
adherence to the intervention, with a particular focus on married but non-pregnant women planning a pregnancy in
the near future.
Trial registration Registered with PROSPERO and ID is CRD42020185033.
*Correspondence:
Sumera Aziz Ali
sa3778@cumc.columbia.edu
Full list of author information is available at the end of the article
© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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Ali et al. BMC Women’s Health (2023) 23:184 Page 2 of 22
Keywords Anemia, Iron therapy, Women of reproductive age, Systematic review, Meta-analysis, Low-middle income
countries
Background Even though several interventions have been shown

Iron deficiency anemia is a significant concern for to reduce the global burden of anemia by 12% between
women of reproductive age (WRA) because it can have 1992 and 2011, such interventions did not benefit WRA
adverse maternal and fetal outcomes [1]. Because of the living in LMICs [28]. In addition, numerous epidemio-
severe consequences of anemia for both WRA and their logical studies, including randomized controlled tri-
offspring, the World Health Organization (WHO) has als (RCTs), are being conducted to evaluate the role of
prioritized iron deficiency anemia on the global health iron in reducing the burden of anemia among WRA in
agenda [2]. The existing literature reveals that anemic LMICs. The findings of these RCTs have been synthe-
pregnant women are more likely to have miscarriages, sized in a few systematic reviews and meta-analyses;
intrauterine growth retardation, preterm births, still- however, these meta-analyses from the last ten years
births, babies born with low birth weight (LBW), and are not without gaps and limitations. For instance, a
neonatal mortality [3–6]. Previous studies, for example, Cochrane review by Low Yuan et al. (2016) assessed
show that a 10 gm increase in hemoglobin levels results the effect of iron therapy in reducing anemia among
in a 30% decrease in maternal deaths, indicating a lin- menstruating women [29]. This review only included
ear relationship between anemia and maternal mortality non-pregnant women and excluded pregnant women
[7]. Similarly, anemia during pregnancy contributes to with a higher burden of anemia during pregnancy and
25% of LBW, 44% of preterm births, and roughly a quar- requiring special care to avoid the negative feto-mater-
ter of stillbirths and neonatal deaths in resource-limited nal outcomes associated with iron deficiency anemia
settings [8]. A meta-analysis found that anemia during [29]. In contrast, another systematic review that was
pregnancy increased the risk of premature birth [9]. Fur- undertaken in 2015 only focused on pregnant women
thermore, according to a WHO multi-country survey, and excluded non-pregnant women [30]. Haider et al.
severe anemia doubles the risk of maternal death [10]. (2013) conducted a meta-analysis to evaluate the effect
While anemia is prevalent among WRA in both high of iron therapy, but the study results were largely based
and low and middle-income countries (LMICs), the latter on observational cohort and quasi-experimental stud-
experience a higher burden of anemia [11, 12]. Anemia ies, which are not free of residual and unmeasured
affects approximately 66.7% of WRA in LMICs, possibly confounding [31]. Finally, rather than studying iron
due to a poor diet caused by food insecurity, parasitic deficiency markers as an outcome, Pasricha et al. (2014)
infections, and decreased iron absorption [13, 14]. Ane- conducted a meta-analysis on iron therapy’s effect on
mia affects roughly half a billion women worldwide, with women’s physical exercise [32].
South-East Asia accounting for 42% of those affected, fol- As previously stated, the limitations of existing
lowed by Africa and the Eastern Mediterranean [15]. In reviews limit the capacity of health professionals and
South Asian and African countries, approximately 50% of decision-makers in LMICs to address the problem of
the burden of anemia among WRA is due to iron defi- iron deficiency in both pregnant and non-pregnant
ciency [16, 17]. For example, the burden of anemia ranges women. Given the existing gaps in the literature, a sys-
between 50 to 90% across diverse states of India [18–20]. tematic review of randomized controlled trials (RCTs)
Similarly, anemia affects 34.5% to 56.8%, 63.1%, and more was required to assess the effect of only iron therapy in
than a third of the WRA in Ethiopia, Uganda, and Bang- reducing anemia, primarily among pregnant and non-
ladesh, respectively [21–24]. pregnant women living in LMICs. Hence, we conducted
While the etiology of anemia is multifactorial, inad- a systematic review and meta-analysis of RCTs to assess
equate iron store as a result of poor nutrition has been the existing evidence on the efficacy of iron therapy in
identified as an important risk factor for anemia among lowering the burden of anemia and improving iron defi-
WRA [25, 26]. Women of reproductive age are more ciency markers among WRA in LMICs. This review will
likely to suffer from iron deficiency due to menstruation, help health professionals, researchers, and decision-
and this risk increases during pregnancy due to increased makers in LMICs make evidence-based decisions when
metabolic demands of pregnancy and fetal growth [25, prescribing iron therapy to WRA. As a result, the high
26]. To address the high prevalence of anemia, the WHO prevalence of iron deficiency anemia among WRAs liv-
proposes to distribute iron supplements to all WRA in ing in resource-limited settings will be addressed.
regions with an anemia burden of more than 20% [27].
Material and methods conducted in hospitals or communities. To include the

Searching strategy most appropriate research articles that meet the eligi-
The updated Preferred Reporting Items for Systematic bility criteria, we used filters on the year of publication
Reviews and Meta-Analyses (PRISMA) guidelines were (2000–2020), gender (females), age of study participants
employed to undertake this review and meta-analysis (15–49 years), language (English), and study designs
for the qualitative and quantitative synthesis of litera- (RCTs).
ture [33]. We focused on reviewing the evidence for the
efficacy of iron as a therapy or intervention to reduce the Intervention and primary outcome
burden of anemia among WRA in LMICs. Using key- Iron therapy in the form of tablets/ syrup/ injectables
words and specific search terms such as Medical Sub- administered daily, weekly, or monthly in the case of
ject Headings (PubMed) and Emtree, a systematic search injectables was proposed as an intervention. In addition,
of three major electronic databases, including Med- we considered interventions that evaluated the effect
line through PubMed, Embase, and Science Direct, was of iron and folic acid supplementation in addition to
undertaken. the usual iron-rich diet. The main outcome is a change
in the mean hemoglobin level. We included RCTs that
used hemoglobin levels (grams per deciliter (g/dL)) to
Eligibility criteria label a WRA as anemic using the WHO proposed cut-
Before conducting a systematic review of the literature offs of hemoglobin level of < 12.0 g/dL or Hct < 36%
and meta-analysis of the studies, we defined eligibility and < 11.0 g/dL or Hct < 33.0% for non-pregnant and
criteria to include the relevant studies undertaken pre- pregnant women respectively (52). The secondary out-
dominantly in LMICs. World Bank’s 2018 guidelines of comes were the prevalence of anemia, mean serum fer-
country classification were used to define a country as ritin, serum transferrin, and serum iron at the end of the
an ‘LMIC.’ The eligibility of a study was contingent on intervention.
being primarily an RCT assessing the efficacy of iron in
decreasing anemia among women aged 15–49 years in
LMICs and being published in the English language in Sources of information and search strategy
a peer-reviewed scientific journal from January 2000 to A systematic literature search was performed electroni-
December 2020. A form to screen the studies based on cally to assess the efficacy of iron as a therapy to reduce
eligibility criteria is given in Table 1. anemia among WRA in LMICs. Two authors searched
Eligibility criteria were categorized into four major the databases independently for studies using a com-
headings using PICO (population, intervention, compari- bination of search terms developed in response to the
son, and outcome) algorithm (Table 2) [34]. The popula- proposed research question. As a first step, four princi-
tion for the current review was women of reproductive pal concepts, including (anemia, WRA, iron therapy, and
age (pregnant and non-pregnant women). The interven- LMICs) were identified. This was followed by using the
tion was considered an iron supplement alone or in com- synonyms of these major concepts, such as low hemo-
bination with folic acid or other micronutrients, taken globin/hematocrit level (anemia), married women/mar-
orally or intravenously in a dosage of 60 to 100 mg daily ried pregnant women/ married non-pregnant women,
for at least one month. To have the potential benefits of iron/iron supplements/iron therapy/iron regimen (Inter-
60 to 100 mg of iron in reducing anemia and improving vention), and developing countries/poor-resource coun-
hemoglobin levels, WRA should have consumed iron for tries/ resource-constrained countries/less developed
at least one month [35]. Since the evidence suggests that countries (LMICs). Besides, we used different spellings of
iron should be taken by WRA for at least 3 to 4 weeks these concepts, such as “anemia vs. anemia” and “hemo-
to show its benefits, we decided to include RCTs where globin vs. hemoglobin.” to obtain appropriate studies.
women were given iron for at least one month [35, 36]. Then, to find more research studies with the same root
Women in the control or comparison group received no word, we combined the major concepts using combina-
iron supplement, a placebo, or any other mineral such as tions (AND, OR) and truncation (*). Further, indexed
zinc, vitamin A, or B12 without iron or a different dose keywords in the Medical Subject Headings (MeSH)
of iron than the defined intervention (details below). The were used to ensure uniform search terms. Initially, the
primary outcome of the review is the improvement in search strategy (shown in Table 3) was developed using
the mean hemoglobin levels of women at the end of the the PICO framework. The search strategy was further
intervention (details below). Lastly, the study design was refined, and finally, the below search strategy was used to
either individual or cluster randomized controlled trials search three databases.
Table 1 Screening form to assess the eligibility of the potential research articles
Study Characteristics Page/
Para/
Figure #
□ Observational study □ Interventional study

• □ Case–control • □ Randomized controlled trial
Type of Study
• □ Cross-sectional • □ Quasi-experimental study

(Interventional studies)
• □ Cohort • □ Pre-post design

□ Qualitative study □ Other design (specify):
• Exploratory
• Descriptive
• Ethnography
• other
Yes □ No □ →Exclude Unclear □

Does the study design meet the criteria for inclusion?
Yes □ No □ Unclear □
Study Participants Describe the participants included:
(Studies involving women of reproductive Are participants defined as women of repro-
age 15–49 years ductive age from 15–49 years? Details:
How is the age or gender defined? Details:
Specific age group and gender (e.g. men /

women):
Do the participants meet the criteria for inclu-

sion?
Study setting: Developing countries Is the study conducted in developing
Follow the list of all developing countries of countries? Specify the region: –––––-
Asia and Africa based on World bank defini- Specify the country:–––––––-
tion of 2018
Does the study measure the efficacy and effec- Yes □ No □ →Exclude Unclear □
Intervention Intervention
(Studies will be included that have measured
the efficacy and effectiveness of iron)
Yes □ No □ →Exclude Unclear□
tiveness of iron in reducing anemia ?
Does the study measure the effects of iron (in
any form) in reducing anemia ?
Yes □ No □ →Exclude Unclear□

Types of outcome measures List outcomes: Give definition of anemia used by author:
(anemia or hemoglobin levels): defined as Do the outcome measures meet the criteria for
Hb < 12.0 g/dl or Hct < 36% among non- inclusion?
pregnant women, and Hb < 11.0 g/dl or

Hct < 33.0% among pregnant women
Year of Publication Is the identified article published between 2000
Yes □ No □ →ExcludeUnclear □
2000 to 2020 and 2020? Specify the year––––-
Language of the published article Is the identified article published in English
Yes □ No □ →ExcludeUnclear □
English language language? Specify the language––––
Type of journal Is the identified journalpeer reviewed?
Peer reviewed journal (Check from the list of all Specify the journal ––––
relevant journals or run a google search)
Include in review □ Exclude from review □

Summary of Assessment for Inclusion
Independently assessed by two authors, and Differences resolved Yes □ No □
Yes □ No □
then compared?
Notes:
“Iron therapy OR iron intervention OR oral iron Study selection

[MeSH Terms]) AND (anemia* OR iron deficiency We used endnote software to handle research articles
anemia*) AND (women OR married women* OR exported from the databases [37]. During the study selec-
pregnant or non-pregnant women*) AND (poor tion process, title and abstract screening were conducted
countries OR developing countries OR low-mid- by two review authors independently. All research arti-
dle-income countries)”. cles were screened by study title using Endnote software,
Table 2 Eligibility criteria according to the PICOS framework

Attribute Inclusion Criteria Exclusion Criteria
Population All studies included women of reproductive age from 15 to Studies involving children or elderly under the age of 15 or over
49 years of age the age of 49 years
Studies involving pregnant or non-pregnant women and married Studies focused on men of any age
or non-married women of reproductive age from 15 to 49 years
of age
Intervention All interventional (experimental) studies have measured the Studies have measured the impact of any other intervention (other
effect of iron therapy on the reduction of anemia than iron) on anemia
Comparison The comparison group is the women who are given interven- Not applicable
tions other than iron or assigned to a placebo
Outcome Anemia is measured objectively and defined as Hb < 12.0 g/dl or Studies that have measured outcomes other than anemia such as
Hct < 36% among non-pregnant women, and Hb < 11.0 g/dl or nutritional deficiencies, food insecurity, etc. as a proxy indicator of
Hct < 33.0% among pregnant women anemia
Study Designs Intervention Studies include both randomized and non-rand- Non-experiment observational quantitative studies (cross-sec-
omized controlled trials tional, case–control, cohort), pre-and post-test designs, com-
mentaries, editorials, symposium proceedings, systematic reviews,
secondary articles, and qualitative studies
Language Studies available in the English Language Studies that are not available in English translation
Period Studies were published between January 2000 to December Studies published before January 2000
2020 to capture a wide range of recently published literature
Type of journal Studies published in peer-reviewed local and international Studies published in non-peer-reviewed journals
journals
Table 3 Search strategy according to PICO criteria
Population ‘women*’ [Mesh] OR ‘women*reproductive age*’ OR pregnant* OR married* OR non-pregnant* OR ‘married woman*’ OR ‘married
pregnant woman’ OR ‘married non-pregnant woman’ OR ‘pregnant women’ ‘reproductive age’ OR ‘non-pregnant women’ ‘reproductive
age’ [Mesh]) AND
Intervention Iron supplements OR Iron therapy OR Iron tablets [MeSH Terms]) OR Iron fish [MeSH Terms]) OR Iron fortification [MeSH Terms]) OR iron
medication [MeSH Terms]) OR iron in any form [MeSH Terms]) OR iron syrup [MeSH Terms]) OR iron rich diet[MeSH Terms]) OR iron rich
fruits, vegetables, meat [MeSH Terms]) AND
Comparison The comparison group is women who are given interventions other than iron or assigned to a placebo
Outcome Anemia OR Hemoglobin levels OR Hemoglobin concentrations OR Hemoglobin status OR low Hemoglobin levels OR low Hemoglobin
concentrations OR ‘low hematocrit levels’ OR Anemia symptoms OR paleness AND
followed by screening the study abstracts of the short- the help of a third evaluator to resolve any conflicts or
listed articles. This was followed by full-text screening discordant information between the data extraction
conducted by two review authors independently. The full processes of two independent reviewers. Furthermore,
texts of the shortlisted articles were then retrieved and existing research studies on the identified topic were
screened against the inclusion and exclusion criteria. A reviewed to identify key items for the data extraction
third reviewer, an expert in the field, resolved disagree- form. The data extraction form includes the follow-
ments between the two. Before ruling any study ineligi- ing items: study name and author with publication year,
ble, both reviewers independently reviewed the full texts study location, sample source, the sample size of both
of the articles, and each reviewer provided strong justifi- intervention and control groups, characteristics of study
cation. The third reviewer made the final decision to con- participants: baseline hemoglobin (g/dl), type of par-
sider an article relevant. The flow diagram generated to ticipants, age category, length of follow-up, intervention
illustrate the study selection process is shown in Fig. 1. type and mode of administration, blinding procedure,
randomization method, and key findings for the primary
Data collection process and secondary outcomes.
Two independent reviewers completed a customized
data extraction sheet for each eligible research article. To Assessment of risk of bias
ensure that all important results and conclusions were Overall quality was assessed using a revised Cochrane
considered in the review, the data extraction tables of risk-of-bias tool for RCTs (RoB 2.0), which assesses
the two independent reviewers were tallied. We enlisted “selection, performance, attrition, detection, and
Fig. 1 PRISMA 2020 flow diagram summarizing the identification and selection of relevant Randomized Controlled Trials
reporting bias by evaluating reported sequence gen- GRADE assessment for overall certainty of the evidence
eration, allocation concealment, blinding of participants Using the GRADE (Grading of Recommendations,
and personnel, incomplete outcome data, selective out- Assessment, Development, and Evaluation), we assessed
come reporting, and other possible sources” [38]. Two the certainty of evidence [39]. The GRADE provides a
independent review authors assessed the risk of bias. reproducible and transparent framework to grade the
The conflict or disagreement between two independent certainty of evidence. Two independent review authors
review authors regarding the risk of bias assessment was assessed GRADE. The GRADE assessment helped to rate
resolved by a thorough discussion between two review- the certainty of the evidence of iron therapy in improv-
ers, and a third reviewer was invited if the two inde- ing anemia. The two authors independently assessed the
pendent reviewers did not resolve the conflict. A high certainty of the evidence for different outcomes such as
risk of bias was recognized if randomization or alloca- serum hemoglobin, ferritin, iron, transferrin, and anemia.
tion concealment was either absent or judged at a higher Since we included all RCTs in the review, the evidence
risk, participants were not blinded, or there was high or was initially set as highly uncertain due to a lack of resid-
imbalanced attrition across the groups. All RCTs that ual confounding. However, to increase our confidence
did not fulfill this criterion were categorized as studies for high certainty of the evidence, we used five additional
with a low risk of bias. We synthesized the findings of the criteria (risk of bias in individual RCTs), inconsistency of
risk of bias, and the degree of bias was rated as low, high, findings between RCTs, indirectness of evidence, impre-
or unclear. A final graph was generated to visualize the cision of the estimate, and publication bias to make a
extent of bias in all eligible studies. Further, we assessed conclusion about the overall certainty of evidence [39].
publication bias by constructing and assessing the asym- We ultimately developed a summary of findings (SoF)
metry of funnel plots. table using GRADE.
A narrative synthesis of eligible studies to quantify heterogeneity. Significant heterogeneity was

Before conducting a quantitative analysis of the same found to exist when I2 was more than 50%, and a p-value
studies, we conducted a narrative synthesis of the eligi- of < 0.05 was used as a criterion for statistically significant
ble studies. To begin, we conducted a descriptive analy- results. Moreover, funnel plots were examined for asym-
sis on all of the final shortlisted full-text RCTs to collect metry to identify publication bias. Because not all studies
information on the authors, publication year, study loca- measured all iron deficiency markers, such as transferrin
tion, sample source, the sample size of both intervention receptor or serum iron levels, we did not include these
and control groups, characteristics of study participants: outcomes in the quantitative synthesis; instead, the find-
baseline hemoglobin (g/dl), type of participants, age cat- ings were summarized using a narrative.
egory, length of follow-up, intervention type and mode
of administration, blinding procedure, and method of Results
randomization. To begin, two reviewers thoroughly read Findings for the study selection process
the full text of the articles to extract data and summarize Five hundred fifty-one RCTs were extracted from various
the key findings. The same reviewers then recorded ana- databases, with 39 duplicates removed and 512 unique
lytical interpretations of the findings to identify impor- RCTs identified for further screening. Based on the eli-
tant emerging themes. Finally, they highlighted the role gibility criteria, 386 irrelevant titles and abstracts were
of iron in decreasing anemia among WRA in LMICs by removed after screening. After reviewing 126 identified
summarizing the relevant findings for the primary and abstracts, 87 studies were removed, including review
secondary outcomes. articles, animal studies, secondary analysis, and in vitro
studies. We read the full texts of 39 records and excluded
Statistical analysis for quantitative results 20 RCTs based on the inclusion and exclusion criteria.
Open Meta[analyst] software was employed to analyze Finally, 19 studies were included in our review and meta-
the data retrieved from all eligible studies [40]. We used analysis (Fig. 1).
the standardized mean difference (SMD) and its respec-
tive 95% confidence interval (CI) to identify differences Study characteristics of the eligible studies
in hemoglobin mean across intervention and comparison A sample size of 19 studies ranged between 50 to 988
groups. We used fixed effects (Mantel–Haenszel method) participants. However, the total sample size in the inter-
and random effects (DerSimonian and Laird method) vention (n = 2230) and control (n = 2281) groups was
meta-analysis models to compute summary estimates comparable. Most studies were conducted in India
for the overall effect of iron. The primary analysis used (n = 10), followed by Pakistan (n = 2) and Bangladesh
a random effects model to generate a pooled effect esti- (n = 2). One study was conducted in Nigeria (n = 1), Viet-
mate for the primary and secondary outcomes. Because nam (n = 1), Tanzania (n = 1), Peru (n = 1), and Indone-
of true differences in the prevalences of causal partners, sia (n = 1). The majority of the studies were conducted
it is reasonable to expect that effects will vary across in hospitals, including antenatal clinics and tertiary care
populations. Since the eligible RCTs were from different OBGYN clinics (n = 14), followed by community-based
international populations, using a random effects model sampling (n = 4) and participants from factory settings
was considered the most conservative analysis. Although (n = 1). Baseline average hemoglobin (g/dl) for the inter-
we used a commonly used fixed effect model at first, the vention group ranged between 8.38 ± 1.41 to 12.5 ± 1.14,
fixed effect model may understate the uncertainty of our and for the control group, it ranged between 8.27 ± 1.20
findings [41]. Furthermore, the fixed effects model gen- to 11.8 ± 1.14. Most participants were aged 16–40 years,
erated narrow confidence intervals that failed to account except for three studies, which had participants aged
for actual variance between studies [41]. Also, the fixed 15–49 years. Two studies included non-pregnant women,
model assumes that studies are drawn from popula- and nine included pregnant women ranging in gesta-
tions with the same effect size, which may not be true tion from 13–26 weeks (2nd trimester). Four studies
for real-world data [42]. On the other hand, the random included women with gestation periods ranging from
effect model assumes that studies are drawn from popu- 12–36 weeks, and two included pregnant women who
lations with varying effect sizes, which seems reasonable were less than 24 weeks gestation at the time of enroll-
[42]. As a result, we kept the results from random-effects ment. The intervention’s effect was observed over a mini-
models rather than the fixed-effects model. Forest plots mum of four weeks of gestation and a maximum of four
were created to visually inspect the degree of hetero- weeks of the post-partum period in pregnant women
geneity and demonstrate individual and pooled effects (n = 17) and 13–26 weeks in non-pregnant women
across eligible RCTs. Q-statistics and I2 were employed (n = 2) (Table 4).
Table 4 Characteristics of the included studies and their main findings for the primary and secondary outcomes (n=19)
Study Age Study Baseline hemoglobin Intervention Comparison Source Type of Type of Duration of Comparison Blinding Randomization Primary Secondary
name (years) location (mean ± SD) group (n) group (n) of participants Intervention intervention group procedure method and outcome outcome
sample level measure* measure**
Intervention Control
group group
Mumtaz 17 to Peri-urban 9.2 ± 1.4 9.5 ± 1.0 100 91 Tertiary > 20 weeks Daily iron 12 weeks of gesta- Twice-weekly Double- Random number Mean Serum Fer-
et al. 35 years and rural care of gestation supplementation iron sup- blind generation hemo- ritin levels
Ali et al. BMC Women’s Health
(2000) Northern hospi- tion capsules plementation globin level significantly

[43] Pakistan tal comprise capsules was sig- increased in
200 mg ferrous comprised nificantly the interven-
sulfate (60 mg of 200 mg higher tion group
elemental iron) ferrous sulfate in the
(60 mg interven-
elemental tion group
iron) (p < 0.001)
(2023) 23:184
Zavaleta 15 to Villa El Sal- 11.6 ± 1.2 11.5 ± 1.4 325 320 Hos- 10 to Daily oral 10 to 24 weeks, 28 The same Double- Random Mean No
et al. 35 years vador/Lima/ pital- 24 weeks of supplements to 30 weeks 37to amount of blind assignment and hemo- statistically
(2000) Peru based gestation of 60 mg Fe 38 weeks, 4 weeks iron and folic stratification globin level significant
[44] (ferrous sulfate) postpartum acid along was not difference
and 250 mg with 15 mg significantly was found
folic acid Zn (as zinc different in S. ferritin
sulfate) in both level and
the groups prevalence
(p > 0.005) of anemia
in both the
groups
Ekström Not Rural areas/ 11.2 ± 1.3 11.0 ± 1.2 74 66 Ante- 18 to Women 12 weeks of gesta- Women Not speci- Not specified No No
et al. men- Mymensingh natal 24 weeks of received weekly tion received fied significant statistically
(2002) tioned thana center gestation 2 doses of sup- daily 1 dose difference significant
[45] (subdistrict), plements/tab- of supple- was found difference
Bangladesh lets comprised ments/tablet in hemo- was found
of 60 mg Fe comprised of globin con- in the
and 250 μg folic 60 mg Fe and centration prevalence
acid 250 μg folic between of anemia
acid the two between the
groups two groups
(p = 0.422)
Page 8 of 22
Table 4 (continued)
group group
Thuy 17 to Vietnam 11.1 ± 0.8 11.0 ± 0.8 64 72 Factory Non-preg- Women 6 months Women Double- Not specified Mean S. Ferritin was
et al. 49 years setting nant women received daily (26 weeks) received daily blind hemo- statistically
(2003) 10 mL of Iron- 10 mL of non- globin level significantly
[46] fortified fish fortified fish was sig- higher in the
sauce fortified sauce nificantly intervention
with 10 mg Fe higher group. The
in the prevalence of
(2023) 23:184
interven- anemia was

tion group statistically
(p < 0.0001) significantly
lower in the
intervention
group. S.
transferrin
receptor was
statistically
significantly
lower in the
intervention
group
Makola Not Tanzania 10.5 ± 1.4 10.5 ± 1.5 127 132 Ante- 12 to Micronutrient- 8 weeks of gesta- Non -fortified Double- Block randomiza- Mean A statically
et al. men- natal 34 weeks of fortified with 11 tion beverage blind tion hemo- significant
(2003) tioned center gestation micronutrients (placebo) globin level increase in S.
[47] including Fe was sig- Ferritin was
nificantly found in the
increased intervention
in the group
interven-
tion group
(p = 0.015)
Mukho- Not India 11.3 ± 1.4 11.6 ± 0.9 40 40 Ante- < 20 weeks Daily oral tablet 32 to 34 weeks Weekly Single- Block randomiza- Mean No second-
padhyay men- natal of gestation of 100 mg gestation oral tablet blinded tion Hemo- ary outcome
et al. tioned clinic elemental iron of 200 mg globin level was assessed
(2004) and 500 mg elemental was not
[48, 49] folic acid iron and significantly
1000 mg folic different
acid between
two groups
(p = 0.11)
Page 9 of 22
Table 4 (continued)
group group
Mukho- Not New Delhi, 40 40 Ante- < 20 weeks 200 mg 32 to 34 weeks of 100 mg Not speci- Block randomiza- Mean Statistically
11.6 ± 0.9 11.3 ± 1.0

padhyay men- India natal of gestation elemental iron gestation elemental fied tion hemo- significant
et al. tioned clinic tablets weekly iron tablets globin level decrease in
(2004) daily was not S. Ferritin
[48, 49] significantly level in the
differed in intervention
both the group and
groups decrease
(2023) 23:184
(p < 0.05) in the

prevalence
of anemia in
the control
group
Sharma 18 to New Delhi, 9.4 ± 0.94 9.6 ± 0.87 100 100 Ante- 18 to Three intra- 37 to 41 weeks of Daily oral Not speci- Partial randomi- Mean Statistically
et al. 40 years India natal 24 weeks of muscular doses gestation dose of fied zation hemo- significant
(2004) clinic gestation of 250 mg 100 mg globin was increase in
[50] elemental Fe elemental Fe improved S. Ferritin
as iron dextran and 500 µg in both level in the
at 1 month folic acid the groups interven-
intervals plus but the tion group.
oral doses of difference Statistical
5 mg folic acid was insig- significant
twice weekly nificant improve-
(p > 0.005) ment in
Serum iron
in both the
groups
Kumar Not India 9.89 ± 0.75 9.60 ± 0.77 75 75 Ante- 16 to Daily oral 36 weeks of gesta- Overall, Not speci- Not specified Mean S. Ferritin was
et al. men- natal 24 weeks of iron therapy tion intramuscu- fied Hemo- statistically
(2005) tioned Clinic gestation of 100 mg of larly 2 doses globin was significantly
[51] elemental iron of 250 mg of improved increasing in
iron sorbitol in the control (par-
with an interven- enteral iron)
interval of 4 tion group group. No
to 6 weeks but the significant
difference difference
between was found
the two in S. iron
groups between the
was not two groups
statistically
significant
(p > 0.05)
Page 10 of 22
Table 4 (continued)
group group
Saha 20 to Chandigarh, 8.47 ± 0.72 8.39 ± 0.74 48 52 Tertiary 14 to One tablet 27 weeks gestation One tablet Double- Not specified Significant Statistically
et al. 40 years India care 27 weeks of once daily of orally twice blind increase in significant
(2007) hospi- gestation Iron polymalt- daily of Fer- the mean increase in S.
[52] tal ose Complex rous Sulphate hemo- Ferritin level
100 mg 60 mg globin in both the
elemental elemental in both groups
iron + folic acid iron + folic groups
(2023) 23:184
500 mcg for acid 500 mcg (p < 0.05)

8 weeks for 8 weeks
Bhutta 15 to Urban and 10.7 ± 1.6 10.8 ± 1.5 466 522 Com- < 24 weeks Multiple Post-natal visit Iron (60 mg) Double- Block randomiza- Mean Statistically,
et al. 49 years rural Sindh/ munity- of gestation micronutrient and folic acid blind tion hemo- significant
(2009) Pakistan based supplements (400 μg) sup- globin level improve-
[53] contained iron plementation was not ment was
30 mg (ferrous tablets significantly found in
fumarate) different S. Ferritin
and folic acid between level in the
(400 μg), retinol the two intervention
(800 μg), zinc groups group
(15 mg), 2 mg (p = 0.27)
of copper,
65 μg of
selenium,
and 150 μg of
iodine, vita-
mins: D (200 IU),
E (10 mg), C
(70 mg), B1
(1.4 mg), B3
(18 mg), B2
(1.4 mg), B6
(1.9 mg), B12
(2.6 μg)
Wijaya- 15 to Karanganyar 12.5 ± 1.14 11.8 ± 1.14 110 117 Com- 12 to Optimized 36 weeks of gesta- Received Not speci- Cluster level Mean Statistically
Erhardt 49 years and Demak, munity- 20 weeks of food was given tion tablets fied hemo- significant
et al. of Central based gestation 6 days per week containing globin decrease in S.
(2011) Java Province, comprised 60 mg of Fe level was Ferritin level
[54] Indonesia 600 g of and 250 mg decreased and S. Iron
tempeh, 30 g of folic acid in both (Fe) level, a
of meat, 350 g the groups significant
of guava, 300 g (p < 0.05) increase in
of papaya, and transferrin
100 g of orange receptor in
along with both the
tablets contain- groups
ing 60 mg of Fe
and 250 mg of
folic acid
Page 11 of 22
Table 4 (continued)
group group
Choud- Not Rural/ Central 10.9 ± 1.4 11.1 ± 1.3 207 198 Antena- 14 to Micronutrient 32 weeks of gesta- Iron and folic Not speci- Cluster level Mean The
hury men- Bangladesh tal care 22 weeks of powder (con- tion acid tablets fied hemo- prevalence
et al. tioned centers gestation tains 60 mg of (60 mg of globin was of anemia

(2012) elemental iron, elemental not sig- improved in
[55] 400 μg of folic iron and nificantly the interven-
acid, 30 mg of 400 μg of folic different tion group
vitamin C, and acid) in the but was
5 mg of zinc) interven- statistically
tion group insignificant
(2023) 23:184
(p = 0.106)
Magon 18 to Rajasthan/ 8.83 ± 1.7 8.38 ± 1.4 45 47 Com- 14 to Weekly distribu- 35–36 weeks of Weekly Single- Consecutively Mean -
et al. 35 years India munity- 16 weeks of tion of leaf gestation distribution blind numbered hemo-
(2014) based gestation concentrate of standard sealed envelopes globin
[56] fortified ready- ready-to-eat along with block level was
to-eat (lcRTE) (sRTE) snack randomization improved
snack in a dried contained in the
powdered 102 g wheat interven-
form fortified flour and 18 g tion group
with 7 g Leaf soya flour significantly
concentrate (p < 0.001)
Kamdi 18 to Maharashtra 8.38 ± 1.41 8.27 ± 1.20 26 24 Health 12 to A single daily 28 days (4 weeks) of The single Double- Stratification and Mean Statistically
et al. 30 years and Gujarat, care 26 weeks of dose of tablet gestation daily dose of blind matching higher significant
(2015) India facility gestation ferrous asparto tablet ferrous levels of rise in S. Fer-
[57] based glycinate (FAG) ascorbate hemo- ritin level in
(contains (contains100 globin the interven-
100 mg of mg of in the tion group
elemental elemental interven-
iron + 300 μg iron + 1.1 mg tion group
of L-methyl of folic acid) (p < 0.01)
folate + 500 μg
of methylco-
balamin)
Mehta 18 to India 10.5 ± 1.2 10.5 ± 1.3 65 71 Health- Non-preg- One non-heme 90 days (13 weeks) No interven- None Cluster level Mean The preva-
et al. 35 years care nant women iron supple- tion (No hemo- lence of ane-
(2017) facility ment bar placebo globin level mia became
[58] based (contain 14 mg either) increased significantly
Fe)/day (termed among lower in
as GudNeSs interven- intervention
bars) tion group group
(p < 0.001)
Page 12 of 22
Table 4 (continued)
group group
Not India 9.38 ± 1 9.49 ± 1 184 184 Com- 12 to Directly 100 days(14 weeks) Unobserved Open-label Block randomiza- Mean Serum
(2023) 23:184
men- munity 16 weeks of observed Iron of gestation IFA sup- tion hemo- ferritin and
tioned based gestation Folic Acid (IFA) plementation globin level reduction of
setting supplementa- tablets daily was higher anemia in
tion tablets in the the interven-
once or twice intervention group
daily tion group was higher
(p < 0.001) but not
significant
16 to Nigeria 11.1 ± 0.9 11.0 ± 0.7 84 80 Ante- 14 to Once daily 37 weeks gestation Twice daily Double Balloting Serum No difference
45 years natal 24 weeks of FeSO4 200 mg FeSO4 blind Hemo- in the serum
clinic gestation supplements 200 mg globin was ferritin levels
in tablets supplements found to between two
form (contains in tablets be lower groups
65 mg elemen- form (contain among
tal Fe) 130 mg of those on
elemental once daily
iron) dose as
compared
to twice
daily
(p = 0.002)
Jose Not India 8.57 ± 0.9 8.67 ± 0.8 50 50 Tertiary 16 to Intravenous 12 weeks gestation Intravenous Open-label Computer Mean rise No
et al. men- care 36 weeks of Ferric Carboxy- Iron sucrose generated block in hemo- significant
(2019) tioned hospi- gestation maltose (FCM) complex randomization globin difference
[59] tal (ISC) found in was found in
FCM group S. Ferritin and
(p < 0.001) S. Iron (Fe)
level in both
the groups
*
Primary outcome measure was defined as change in Hemoglobin (Hb) level
**
Secondary outcome measures were defined as changes in the mean ferritin level, serum transferrin receptor, iron status, and iron deficiency
Page 13 of 22
Interventions included primary outcome (hemoglobin) and one secondary out-

Seven of the 19 RCTs were based on oral iron tablets to be come (Serum ferritin). A total of 19 studies (n = 4421
administered daily [42–44, 48, 51, 52, 57, 60]. Two studies participants) were included in the meta-analysis to
included oral iron tablets as a weekly dose [45, 49]. Two estimate the effect size. Meta-analysis indicated over-
studies compared the efficacy of parenteral administration all pooled effect estimate for the role of iron therapy in
of iron supplementation [50, 59]. In one trial, ferric carbox- lowering the burden of anemia among the WRA group
ymaltose was given intravenously (IV) and compared with was -0.71 (95% CI: -1.27 to -0.14) (p = 0.008). The het-
IV iron sucrose complex [59]. Another trial provided an erogeneity (I2) across included studies was found to be
intervention based on three intramuscular doses of 250 mg statistically significant, as indicated by the parameters
elemental iron at intervals of 1 month along with the oral of heterogeneity (Q = 746.93, I2 = 97.59%, p = 0.000)
doses of 5 mg folic acid twice weekly and compared with a (Fig. 2).
daily oral dose of 100 mg iron and 500 µg folic acid [50]. Of Figure 2 depicts the overall findings showing that iron
the total, three studies included micronutrient supplements therapy positively affects hemoglobin levels. More spe-
comprised of zinc, minerals (copper, selenium), retinol, cifically, iron therapy in any form increased mean hemo-
iodine, Vitamins: D, E, C, B1, B3, B2, B6, and B12 in differ- globin levels by 0.40 gms. The intervention arm’s mean
ent doses, along with iron and folic acid as an intervention and standard deviation for hemoglobin was 11.14 ± 1.11
and two out of three studies compared with iron (60 mg) gm/dl, while the comparison group’s mean and stand-
and folic acid (400 μg) supplementation tablets and one ard deviation for hemoglobin was 10.74 ± 1.019 gm/dl.
study provided non-fortified beverage as a placebo [47, 53, However, there were variations in the results of individ-
55]. Four studies out of 19 included an optimized prepara- ual studies. For instance, nine studies found that mean
tion based on food and snacks in the form of bars, sauce, hemoglobin levels improved in the intervention group
fortified ready-to-eat snacks in dried powdered form, and significantly [43, 46, 47, 52, 56–60]. Eight RCTs found
one study included meat, fresh fruits, and vegetable along that the mean hemoglobin level was not significantly dif-
with iron tablets (60 mg), and folic acid (250 mg) as shown ferent between the two groups post-intervention [44, 45,
in Table 4 [46, 54, 56, 58]. 48–51, 53, 55]. One study showed that the mean hemo-
globin level decreased significantly in both groups [54].
Pooled effect for outcomes measurement Another study documented that the hemoglobin level
Pooled effect for the primary outcome, serum hemoglobin was decreased in the intervention group after comparing
Since the complete data were only available for the once-daily (intervention group) vs. twice-daily (control
hemoglobin, we performed quantitative analysis for the group) oral supplementation [42].
Fig. 2 Forest plot summarizing the overall pooled effect of iron supplementation on the primary outcome, hemoglobin (n = 19)
Findings for the secondary outcomes of the fourteen studies found statistically significant
The included studies assessed secondary outcomes, improvements in mean serum ferritin levels in the
including changes in mean serum ferritin level, serum intervention group versus the control group [43, 46,
transferrin receptor, serum iron, and improvement in 47, 50, 53, 57]. One RCT found significant improve-
iron deficiency anemia. ment in the mean serum ferritin levels across both
groups [52]. In contrast, one study documented a
Pooled effect for the secondary outcome, serum ferritin levels significant increase in the mean serum ferritin levels
For the secondary outcomes, complete data were only in the control group [51]. One RCT found a signifi-
available for serum ferritin; therefore, we performed cant reduction in the mean serum ferritin levels in
a quantitative analysis for serum ferritin. A total of 15 both groups [54], whereas one RCT noticed a sub-
studies (n = 3648 participants) were included in the stantial reduction in the mean serum levels in the
meta-analysis to estimate the effect size. Meta-analysis intervention group than the control group [49]. 4
indicated overall pooled effect estimate for the role of RCTs identified no significant difference in the mean
iron therapy in improving the ferritin levels among WRA serum ferritin levels between the two groups [42, 44,
was -0.76 (95% CI: -1.56 to 0.04) (p = 0.04). The hetero- 59, 60].
geneity (I2) across included studies was found to be sta-
tistically significant, as indicated by the parameters of Reduction in the anemia prevalence
heterogeneity (Q = 659.95, I2 = 97.88%, p = 0.000) (Fig. 3). Six randomized controlled trials investigated the
Overall, the results revealed a favorable effect of iron reduction in the prevalence of anemia as an outcome
therapy in improving serum ferritin levels, as shown in of interest. Two out of six RCTs reported a significant
Fig. 3. More precisely, in simple terms, iron therapy in decrease in the prevalence of anemia in the interven-
any form improved the mean ferritin levels by 5.90ug/L. tion group compared to the control group [46, 58].
The mean and standard deviation for ferritin levels of the While two other RCTs showed an improvement in
intervention arm was 37.61 ± 20.0, whereas the mean and anemia in the intervention than the control group, the
standard deviation for ferritin levels of the comparison findings were statistically non-significant [55, 60]. Two
group was 31.71 ± 20.13. However, there were variations RCTs did not find a significant difference in the preva-
in the results of individual studies. lence of anemia across both groups [44, 45]. And one
RCT showed negative findings, meaning a significant
Change in mean serum ferritin levels: qualitative synthesis decline in the prevalence of anemia was observed in the
Fourteen studies measured mean serum ferritin lev- control group than in the intervention group, as shown
els after the intervention as a secondary outcome. Six in Table 4 [51].
Fig. 3 Forest plot summarizing the overall pooled effect of iron supplementation on the secondary outcome, Serum Ferritin (n = 15)
Change in mean serum iron Publication bias

Four out of 19 RCTs assessed change in serum iron levels A graphical representation, a funnel plot, was employed
post-intervention, and two trials reported no significant to assess publication bias, indicating potential bias
difference in the mean serum iron between both groups because the shape of the graph is not symmetrical,
[51, 59]. One RCT reported significant improvement in as shown in Fig. 4a and b for studies that assessed pri-
the mean serum iron levels in both groups [50]. In con- mary (hemoglobin) and secondary outcomes (ferri-
trast, another RCT identified a statistically significant tin), respectively. Since the funnel plot is subjective, we
reduction in the mean serum iron in both groups [54]. used a confirmatory objective statistical test (i.e., Egger’s
test) to evaluate the publication bias. The objective test
results for the primary outcome revealed no publication
Change in serum transferrin receptor bias as the t-test was not statistically significant (Egger
Two of the 19 RCTs examined the change in serum trans- t-test = -1.7, p = 0.107), as shown in Fig. 4a. However,
ferrin receptor after an intervention, with one finding the same objective test was statistically significant for the
that serum transferrin receptor was significantly lower serum ferritin (Egger t-test = -2.41, p = 0.032), suggesting
in the intervention group than in the control group [46]. a publication bias (Fig. 4b).
However, another RCT reported increased serum trans-
ferrin receptors in both groups [54]. Summary of findings using GRADE assessment
Since the meta-analysis was conducted on RCTs, the
overall certainty of the evidence was considered rea-
Overall Quality assessment for RCTs
sonable. However, using the additional five criteria of
Table 5 depicts the overall quality assessment of the eli-
GRADE, the certainty of the evidence was assessed for
gible RCTs. Overall, 6 of 19 studies were deemed to have
five outcomes, and SoF is provided in Table 6. The find-
a low risk of bias based on criteria such as the low risk of
ings reveal overall certainty of the evidence for outcomes
randomization, allocation concealment, or blinding [42–
such as serum hemoglobin, serum ferritin, and anemia
44, 53, 54, 57]. Of the total, seven studies were found to
prevalence was moderate. This implies that the two inde-
have a high risk of bias since the randomization method
pendent authors believe that the truth or true effect size
was unclear [45, 46, 51, 52, 54, 55, 58]. A high risk of bias
is probably close to the estimated effect size, and future
was found in 2 studies where no allocation concealment
research for similar outcomes may change the estimate
was done [58, 59], and in 8 studies, concealment was
for the effect size. However, the certainty of the evidence
unclear [45–51, 55]. The absence of blinding was found in
for outcomes such as serum iron and transferrin receptor
4 studies [56, 58–60]. An unclear description of blinding
was low, suggesting that further research for these two
study participants or outcome assessors was found in 5
outcomes will likely change the estimate of the effect.
studies [45, 48–51, 54, 55] and, subsequently, labeled as
having a high overall risk of bias.
Fig. 4 A Funnel plot to evaluate the publication bias among included studies in the meta-analysis for the primary outcome, hemoglobin (n = 19).
B Funnel plot to evaluate the publication bias among included studies in the meta-analysis for the secondary outcome, Serum Ferritin (n = 15)
Table 5 Risk of bias assessment of the studies included in the meta-analysis (n = 19)
Randomization Allocation Blinding of Blinding of Incomplete Selective Other bias
Method Concealment participants and outcome outcome outcome
personnel assessors data reporting
Mumtaz et al. 2000 [43]
Zavaleta et al. 2000 [44]
Ekström et al. 2002 [45]
Thuy et al. 2003 [46]
Makola et al. 2003 [47]
Mukhopadhyay et al. 2004

[48, 49]
Mukhopadhyay et al. 2004
[48, 49]
Sharma et al. 2004 [50]
Kumar et al. 2005 [51]
Saha et al. 2007 [52]
Bhutta et al. 2009 [53]
Wijaya-Erhardt [54]
Choudhury et al. 2012 [55]
Magon et al. 2014 [56]
Kamdi et al. 2015 [57]
Mehta et al. 2017 [58]
Jose et al. 2019 [59]
Discussion reduces the burden of anemia and iron deficiency, raises

We conducted this systematic review and meta-analysis hemoglobin levels, increases iron stores, improves exer-
to assess the role of iron therapy in reducing anemia in cise ability, and decreases fatigue. [29]. Likewise, another
pregnant and non-pregnant women. The review’s find- review conducted five years ago also revealed similar
ings showed that iron supplementation helps to improve findings, where authors found positive effects of iron on
markers of iron deficiency anemia, such as serum ferri- hematological and pregnancy outcomes [30]. However,
tin and hemoglobin levels. The current systematic review this review relied on studies with very low-quality evi-
and meta-analysis findings are consistent with previ- dence [30]. A review by Haider et al., carried out in 2013,
ous reviews. Low Yuan et al., for example, conducted a showed consistent findings. Haider et al. emphasized the
review in 2016 to assess the effectiveness of iron therapy role of iron in improving birth weight rather than inter-
in reducing anemia in menstruating women [29]. The mediate outcomes such as improving anemia or markers
authors demonstrated that daily iron supplementation of iron deficiency [31]. Regardless of these differences,
the analogous findings across these reviews indicate the settings with a greater hematological response [70]. In
role of iron in improving hemoglobin and other markers addition, improving iron stores during pregnancy may
of iron-deficiency anemia among WRA. also decrease the risk of mortality resulting from hem-
The current review and meta-analysis findings are bio- orrhage and may lead to improved hemoglobin and iron
logically plausible, and several mechanisms regulating levels after pregnancy [9].
iron absorption have been explored in different studies
[61–63]. More precisely, the findings suggest that daily Strengths and limitations
iron supplementation appears to be an effective inter- This review’s main strength is that it provides insights
vention to reduce the burden of anemia among WRA. into the effect of iron on a wide range of outcomes,
This review’s findings complement those of other studies including hemoglobin, serum ferritin, iron, transferrin
examining the role of iron supplements in reducing ane- receptor, and anemia prevalence. In addition, unlike other
mia in pregnant and non-pregnant women. Based on the reviews, we included all studies from LMICs that looked
results of this review and reasonably comparable find- at the role of iron therapy in any form among pregnant
ings from other reviews, iron, in any form, for pregnant and non-pregnant women. In addition, by including only
or non-pregnant women may be beneficial in reducing RCTs, the problem of the unknown and unmeasured
the burden of maternal anemia. The question arises of confounding could be addressed, thereby improving the
how such intervention improves hemoglobin levels. Iron confidence in the validity of the findings. Additionally, no
absorption in intestinal cells, followed by iron transfer to significant publication bias was found in our meta-analy-
bone marrow, muscles, and other tissues, could be one sis, indicating that most trials with positive, negative, or
possible answer to the proposed question. Iron is taken null findings were published in the literature.
up by receptors in these tissues and used for various bio- However, some inherent limitations of the individual
logical functions or stored [64]. Both animal and human eligible studies need to be considered while interpreting
studies reveal an inverse relationship between iron status the findings of this review. For example, high-quality stud-
or stores and the ability to absorb iron from intestinal ies included in this review and meta-analysis were rela-
cells [65]. This implies that an iron-deficient woman has tively less (n = 5) because of methodological issues in the
the potential to absorb iron two times more than an iron- randomization methods, no or unclear allocation conceal-
non-deficient woman because iron deficiency induces ment, and lack of blinding. Moreover, the heterogeneity
changes in the transport of iron across the intestine [65]. was found to be very high, which could be explained by
Furthermore, the evidence suggests that an iron- factors such as variation in sample size, differences in the
deficient individual should aim to increase hemoglobin follow-up time, differences in the populations (pregnant
concentrations by 1 g/dl every week and be aware of the and non-pregnant women), and substantial variations
dietary sources that inhibit iron absorption [29]. Iron in the interventions designed (difference in dosages and
absorption from supplements follows the same princi- composition, and duration of interventions). There was a
ples as iron absorption from dietary sources, and con- significant variation in the given interventions, for exam-
suming vitamin C, meat, and acidic foods increases iron ple, daily iron supplementation vs. weekly, once-daily vs.
absorption [66]. Tannins, calcium, and phytates reduce twice daily, oral iron vs. parenteral iron, micronutrient
the absorption and should not be consumed alongside powder and/or iron vs. only iron, fortified snacks in addi-
iron [66]. In addition to the dietary resources, one needs tion to iron vs. placebo, resulting in heterogeneous expo-
to be aware of the geographical regions before provid- sure. In addition, we included studies from 2000 to 2020,
ing iron. For example, health professionals may need to which is a relatively long period with a greater degree of
treat malaria in areas with endemic malaria while provid- variation in the methods of different RCTs. The purpose
ing iron therapy to women [67]. Similarly, iron may also of including the more extended period was to capture
be affected by worm infestation. Therefore, healthcare multiple RCTs on the role of iron in improving anemia
professionals should consider deworming women before among WRA. However, considering a longer period may
prescribing iron therapy to WRA [68]. This suggests that lead to a more significant heterogeneity due to a wide
iron therapy may be beneficial when healthcare profes- variation in the methods. While it may be challenging to
sionals become cognizant of the facts mentioned above avoid heterogeneity entirely, RCTs can be designed effi-
while prescribing iron therapy to a woman. ciently to assess the role of uniform dose and form of iron
Evidence from epidemiological studies shows that and to follow women for the same time in different set-
women from LMICs enter pregnancy with limited iron tings. This will aid in determining the effect of only iron
stores and lower hemoglobin levels than those from supplements versus a placebo in the control group to iso-
high-income countries [69]. Therefore, the demand for late the effect of a fixed dose of iron in reducing anemia.
iron absorption is higher in women from resource-poor Furthermore, although we identified potential secondary
Table 6 Summary of findings (SoF) table illustrating the summary on certainty of overall evidence for five outcomes using GRADE
Outcomes Number of Effect size and 95% CI Certainty of the evidence Comments
participants (GRADE)a
(RCTs)
Mean Serum hemoglobin 4421 (19) -0.71 (-1.27 to -0.14) Moderat The assessment of certainty by two
authors concludes that effect size for
the serum hemoglobin is precise and
consistent with low risk of bias at out-
come level, suggesting that the true
effect size for serum hemoglobin is
probably close to the estimated effect
Mean Serum Ferritin 3648 (15) -0.76 (-1.56 to 0.04) Moderate The authors believe that effect size for
the serum ferritin is precise and con-
sistent with low risk of bias at outcome
level, suggesting that the true effect
size for serum ferritin is probably close
to the estimated effect
Anemia Prevalence 1910 (6) Could not be estimated Moderate While the effect size for anemia could
not be calculated, the authors believe
that narrative regarding anemia preva-
lence suggested that anemia declined
in the intervention group. Since the
evidence was direct, consistent with
no risk of bias at the outcome level,
the authors believe that certainty of
evidence is moderate for the anemia
outcome
Mean serum iron levels 677 (4) Could not be estimated Low Since the authors could not estimate
the effect size and the findings for iron
are from very few studies with incon-
sistent results, the authors believe that
certainty of evidence for iron is low
and needs to be explored more in the
future
Mean serum transferrin receptor 363 (2) Could not be estimated Low Since the authors could not estimate
levels the effect size for the serum transferrin
and the findings for serum transferrin
are from very few studies with incon-
sistent results, the authors believe that
certainty of evidence for serum trans-
ferrin is low and needs to be explored
more in the future
Very low: The truth or true effect size is totally different from the estimated effect size
Low: The true effect may be markedly different from the estimated effect size
Moderate: The authors believe that the truth or true effect size is probably close to the estimated effect size
High: The authors’ confidence is high, and they believe that the truth or true effect size is very similar to the estimated effect size
a
GRADE certainty ratings
outcomes such as iron and transferrin receptors, most form, increases hemoglobin levels in pregnant and non-
RCTs did not measure the secondary outcomes we chose. pregnant women and reduces iron deficiency anemia, as
Hence, the effect size for outcomes sucn as iron and trans- evidenced by increases in hemoglobin, serum ferritin,
ferrin receptors could not be estimated. Finally, we only and decreased soluble transferrin receptors. The review
included RCTs published in English, limiting our ability to also revealed that WRA in resource-constrained settings
have inferences from studies published in other languages. could be given iron in any form. The findings of this sys-
tematic review and meta-analysis may help physicians,
Conclusions researchers, and policymakers make informed decisions
This review aimed to determine the effect of iron on about providing iron therapy to pregnant and non-preg-
hemoglobin levels and anemia in women of reproductive nant women and prepare them with enough iron stores
age. Overall, the review found that iron therapy, in any for adequate fetal growth.
Clinical and research implications Supplementary Information

The current review and meta-analysis findings can be The online version contains supplementary material available at https://doi.
used to treat anemia among WRA in LMICs using sim- org/10.1186/s12905-023-02291-6.
ple iron therapy in oral or injectable forms, depending
Additional file 1. Data extracted for Risk of Bias Assesment.
on the severity of anemia and a woman’s needs. Simple,
cost-effective, and culturally appropriate iron and folic
acid therapies can be given to women before or during Acknowledgements
None
pregnancy to reduce the anemia burden. This improves
hemoglobin and iron stores, as evidenced by an increase Authors’ contributions
in ferritin levels, a marker of iron stores. The study was conceptualized by SuA & SaA. The overall supervision of
work was done by SuA and SuA also performed the analysis and wrote the
Although current evidence suggests that iron is impor- first draft manuscript. The second author, SR, extracted and synthesized the
tant for WRA in LMICs, more research is needed to fill results from the data provided through searched literature and helped in pre-
important gaps. For example, none of the eligible RCTs paring the first draft of the manuscript. SaA did the literature search for the
introduction and discussion and edited the draft. AA, AAA, and SN carried out
examined the underlying mechanisms by which iron can the literature search, reviewed the articles, and compiled all the literature. FR
improve outcomes. There is a need to evaluate the ben- reviewed the literature, provided their expert clinical opinions, and reviewed
efits and side effects of iron and adherence to iron intake and edited the manuscript. The new author (NK) provided her expert clinical
opinion on the topic, and she offered her guidance to address the comments
because there is a dearth of evidence on these outcomes. of the reviewers. She provided her intellectual support and helped us to
Further, almost all of the RCTs focused on improving improve the manuscript. She helped us to modify the manuscript as per the
iron status during pregnancy rather than during a criti- reviewer’s comments. NK also did an additional literature search to update
the discussion session. NK also read and edited the revised manuscript and
cal preconception window when a woman can lay a good approved the same for resubmission. All authors have contributed to this
foundation for an upcoming baby by eating iron-rich manuscript and reviewed and approved the final version of the paper.
foods or taking iron supplements. Thus, more research is
Funding
needed in public health settings to assess the role of iron There is no funding for this work.
before and during pregnancy on iron markers as well
as distal birth outcomes such as birth length and birth Availability of data and materials
This review was based on the synthesis of findings from the existing published
weight. RCTs and the references of those RCTs are mentioned in the reference list. Any-
In LMICs, iron supplementation is usually combined one who needs raw data of individual studies can directly contact the authors
with folic acid and/or other micronutrients. As a result, of individual studies or can retrieve the data from the published articles. All
RCTs are properly cited in the references and a reference list can be used to
it is unclear how much improvement in anemia can access the RCTs online. However, we have uploaded the supplementary files of
be attributed to iron alone. Thus, more well-designed extracted data that were used for the analysis and risk of bias assessment.
RCTs are needed to fully understand the efficacy and
safety of iron alone in reducing anemia among WRA Declarations
in LMICs. Finally, secondary outcomes such as serum
Ethics approval and consent to participate
ferritin, serum transferrin receptor, and transferrin sat- Not applicable as this was a systematic review and meta-analysis of published
uration indicate a long-standing and sustained param- RCTs.
eter of storage iron, and their depletion can result in
Consent for publication
iron deficiency. Hence, RCTs should measure these Not applicable.
outcomes rigorously after interventions are given for a
reasonable time to identify long-term iron stores [71]. Competing interests
The authors declare no competing interests.
Furthermore, serum ferritin, serum transferrin recep-
tor, and transferrin saturation have been shown to be Author details
1
more accurate indicators of iron deficiency anemia. As Department of Epidemiology, Columbia University, New‑York, USA. 2 Divison
of Environment and Sustainability, The Hong Kong University of Science
a result, estimating these parameters will reveal long- and Technology, Hong Kong, People’s Republic of China. 3 Faculty of Nursing,
term benefits [72]. University of Alberta, Alberta, Canada. 4 Aga Khan University Hospital, Karachi,
Pakistan. 5 CMH Institute of Medical Sciences, Bahawalpur, Pakistan. 6 Liaquat
University of Medical and Health Sciences, Jamshoro, Pakistan.
Abbreviations
LMICs Low-middle-income countries Received: 9 December 2021 Accepted: 20 March 2023
LBW Low Birth Weight
PICOS Population, Intervention, Comparison, Outcome, and Setting
PRISMA-P Preferred Reporting Items for Systematic Reviews and Meta-Analy-
ses Protocols
RCTs Randomized Controlled Trials References
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Ali et al.

BMC Women’s Health (2023) 23:184 BMC Women’s Health

RESEARCH Open Access

Role of iron in the reduction of anemia

Background Even though several interventions have been shown

Material and methods conducted in hospitals or communities. To include the

□ Observational study □ Interventional study

• □ Cross-sectional • □ Quasi-experimental study

• □ Cohort • □ Pre-post design

Yes □ No □ →Exclude Unclear □

Yes □ No □ →Exclude Unclear □

Yes □ No □ →Exclude Unclear □

Yes □ No □ →Exclude Unclear□

Yes □ No □ →Exclude Unclear □

Include in review □ Exclude from review □

Independently assessed by two authors, and Differences resolved Yes □ No □

“Iron therapy OR iron intervention OR oral iron Study selection

Table 2 Eligibility criteria according to the PICOS framework

Table 3 Search strategy according to PICO criteria

A narrative synthesis of eligible studies to quantify heterogeneity. Significant heterogeneity was

(2000) Northern hospi- tion capsules plementation globin level significantly

interven- anemia was

11.6 ± 0.9 11.3 ± 1.0

(p < 0.05) in the

500 mcg for acid 500 mcg (p < 0.05)

et al. tioned centers gestation tains 60 mg of (60 mg of globin was of anemia

Interventions included primary outcome (hemoglobin) and one secondary out-

Change in mean serum iron Publication bias

Mumtaz et al. 2000 [43]

Zavaleta et al. 2000 [44]

Ekström et al. 2002 [45]

Thuy et al. 2003 [46]

Makola et al. 2003 [47]

Mukhopadhyay et al. 2004

Kumar et al. 2005 [51]

Saha et al. 2007 [52]

Bhutta et al. 2009 [53]

Choudhury et al. 2012 [55]

Magon et al. 2014 [56]

Kamdi et al. 2015 [57]

Mehta et al. 2017 [58]

Jose et al. 2019 [59]

Discussion reduces the burden of anemia and iron deficiency, raises

Clinical and research implications Supplementary Information

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