nutrients
Article
Prevention and Management of Iron Deficiency/Iron-Deficiency
Anemia in Women: An Asian Expert Consensus
Rishma Dhillon Pai 1 , Yap Seng Chong 2 , Lyra Ruth Clemente-Chua 3 , Rima Irwinda 4 ,
Trang Nguyen Khanh Huynh 5 , Noroyono Wibowo 4 , Maria Corazon Zaida Gamilla 6
and Zaleha Abdullah Mahdy 7, *
Citation: Pai, R.D.; Chong, Y.S.;
Clemente-Chua, L.R.; Irwinda, R.;
Huynh, T.N.K.; Wibowo, N.; Gamilla,
M.C.Z.; Mahdy, Z.A. Prevention and
Management of Iron Deficiency/
Iron-Deficiency Anemia in Women:
An Asian Expert Consensus.
Nutrients 2023, 15, 3125. https://
doi.org/10.3390/nu15143125
Academic Editor: Edith Lahner
Received: 4 June 2023
Revised: 27 June 2023
Accepted: 10 July 2023
Published: 13 July 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Nutrients 2023, 15, 3125. https://doi.org/10.3390/nu15143125
1 Department of Obstetrics and Gynaecology, Lilavati Hospital, Mumbai 400050, India; rishmapai@hotmail.com
2 Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore 117597, Singapore; obgcys@nus.edu.sg
3 Department of Obstetrics and Gynecology, The Medical City, Pasig 1605, Philippines;
lyraruthcchua@gmail.com
4 Fetomaternal Division, Department of Obstetrics and Gynecology, Faculty of Medicine, University of
Indonesia—Cipto Mangunkusumo Hospital, Jakarta 10430, Indonesia; rima.irwinda@yahoo.com (R.I.);
wibowonoroyono@yahoo.com (N.W.)
5 Department of Obstetrics and Gynecology, Pham Ngoc Thach University of Medicine,
Ho Chi Minh 700000, Vietnam; tranghnk08@gmail.com
6 Department of Obstetrics and Gynecology, University of Santo Tomas Hospital, Manila 1008, Philippines;
zngamilla_md@yahoo.com
7 Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia,
Kuala Lumpur 56000, Malaysia
* Correspondence: zaleha@ppukm.ukm.edu.my
Abstract: The lack of standardized clinical practice impeding the optimal management of iron de-
ficiency (ID) and iron deficiency anemia (IDA) in women is a global concern, particularly in the
Asia-Pacific region. The aim of this study was to determine best practices through a Delphi consen-
sus process. In Round 1, panelists were asked to rate their level of agreement with 99 statements
across four domains: identification, diagnosis and assessment, prevention, and treatment of ID/IDA
in women. In Round 2, panelists reappraised their ratings in view of the collective feedback and
responses to Round 1. After two rounds, consensus (≥85% agreement) was reached for 84% of the
Delphi statements. Experts agreed on the role of presenting symptoms and risk factors in prompting
assessments of anemia and iron status in women. Experts repeatedly called for prevention, recom-
mending preventive iron supplementation for pregnant women irrespective of anemia prevalence
levels, and for non-pregnant adult women, adolescent girls, and perimenopausal women living in
areas with a high prevalence of anemia. Experts unanimously agreed to prescribing oral ferrous
iron as first-line therapy for uncomplicated ID/IDA. The recommendations and clinical pathway
algorithms generated should be used to inform clinical practice and standardize the care of women at
risk or presenting with ID/IDA in the Asia-Pacific region.
Keywords: iron deficiency; iron deficiency anemia; women; Delphi; consensus
1. Introduction
Iron deficiency (ID) is one of the most common micronutrient deficiencies that dis-
proportionately affects females throughout their lifecycle via menstruation (blood loss),
pregnancy (fetal demands), and bleeding in childbirth [1–3]. Iron deficiency occurs as a
spectrum, ranging from iron depletion without anemia to impaired erythropoiesis and
anemia [4]. In 2019, anemia affected 1.8 billion people worldwide; ID is the predominant
cause [5]. Of concern, this estimate does not begin to account for the many cases of ID in
the absence of anemia [6]. Females, especially those in developing regions, are particularly
vulnerable to ID, and anemia due to ID is the leading cause of years lived with disability
https://www.mdpi.com/journal/nutrients
Nutrients 2023, 15, 3125 2 of 14

among women of reproductive age in low- and middle-income countries [3,5,7]. According
to the World Health Organization (WHO) estimates for 2016, anemia was diagnosed in
32.5% of non-pregnant women, 40.1% of pregnant women, and 32.8% of women of repro-
ductive age, with Southeast Asia being the region with the highest prevalence of anemia in
all three subgroups of women [8].
Iron serves an integral role in key cellular processes, including energy metabolism, cell
signaling, gene expression, immunity, and cell growth regulation and differentiation [1,4,9].
Therefore, it is important to recognize that symptomatic ID can occur without anemia [10].
The systemic consequences of ID in women are extensive and potentially serious if left
untreated [4,7]. In addition to the well-known features of anemia, ID can lead to non-
hematological symptoms, which have often been overlooked. These can include fatigue,
reduced physical endurance, hair loss, brittle nails, defective structure or function of
epithelial tissues, pica, restless legs syndrome, decreased cognitive performance, and
behavioral disturbances [4]. ID in women impairs overall health and quality of life; it is
associated with an increased risk of adverse maternal and neonatal outcomes [4].
The enduring burden of anemia in women suggests that ID in women is still inade-
quately assessed, diagnosed, and treated to prevent progression to iron deficiency anemia
(IDA) [7,9]. In 2014, the WHO set a goal of reducing anemia in women of reproductive age
by 50% by 2025; this and other global targets for improving maternal, infant, and young
child nutrition have since been extended to 2030 [1,3,11]. The WHO recommends intermit-
tent or daily iron and folic acid supplementation as a public health intervention to improve
iron status and reduce the risk of anemia in women of reproductive age, depending on
pregnancy and postpartum status, menstruation, population-level prevalence, and the
diagnosis of chronic disease or infection [3,12].
Despite the progress made, the absence of clear clinical guidance that focuses on
women has led to considerable variations in clinical practice and patient outcomes. There-
fore, the aim of this Delphi consensus was twofold: (1) to generate high-quality expert
consensus statements; and (2) to develop clinical pathway algorithms for the identifica-
tion, assessment, prevention, and treatment of ID/IDA in four key subgroups of women
(i.e., pregnant women, non-pregnant adult women, adolescent girls, and perimenopausal
women) presenting to the obstetrics and gynecology clinic in the Asia-Pacific region.

2. Materials and Methods

2.1. Study Design and Expert Panel
This paper uses the term ‘Delphi consensus’, referring to a systematic process of
gaining consensus through controlled feedback by a group of experts recognized for their
knowledge and experience in the subject matter. The ‘Delphi technique’ is used to describe
the steps of the Delphi method applied in the process. ‘Delphi rounds’ refers to the iterative
rounds of survey questionnaires sent to the panel members.
In view of the limited high-quality evidence around ID/IDA prevention and man-
agement in women, we employed a two-round Delphi technique (Figure 1). The Delphi
technique has been applied across a wide range of medical disciplines to establish con-
sensus and guide clinical practice, including the field of ID [13–17]. The modified Delphi
technique, an approach that requires an in-person or virtual meeting to finalize consen-
sus [18], was not considered for this study because it was challenging to schedule a time
when all panelists could participate. Furthermore, this was a deliberate decision to allow
authors adequate time to review the relevant literature and results of each Delphi round.
For this Delphi consensus, we assembled an expert panel composed of eight leading
clinician–researchers representing obstetrics, gynecology, and women’s health from India
(n = 1), Indonesia (n = 2), Malaysia (n = 1), Philippines (n = 2), Vietnam (n = 1), and
Singapore (n = 1). Members of the expert panel were selected based on the following criteria:
a practicing obstetrician–gynecologist with more than 15 years of experience; a regionally
or nationally recognized expert in obstetrics and gynecology; considerable experience
in the diagnosis, evaluation, and management of ID/IDA; previous experience as an
Nutrients 2023, 15, 3125 3 of 14

advisory board member; and an editorial board member for a reputable regional journal.
The Delphi surveys were administered anonymously to the panel between February and
September 2022 using SurveyMonkey (www.surveymonkey.co.uk, accessed on 2 January
2022). Notably, all panelists were asked to provide feedback based on their perspectives,
Nutrients 2023, 15, x FOR PEER REVIEW 3 of 14
experience, and the latest literature, with the goal of improving practices across the Asia-
Pacific region.

Figure 1. Overview of Delphi survey rounds. * Two statements that did not reach consensus in
Figure 1. Overview of Delphi survey rounds. * Two statements that did not reach consensus in
Round 1 were removed.
Round 1 were removed.
For this Delphi
2.2. Development consensus,
of Items for Roundwe1assembled
of the DelphianSurvey
expert panel composed of eight leading
clinician–researchers representing obstetrics, gynecology, and women’s health from India
The statements for Delphi Round 1 were developed from a review of the litera-
(n = 1), Indonesia (n = 2), Malaysia (n = 1), Philippines (n = 2), Vietnam (n = 1), and Singapore
ture. The PubMed database was searched for full-text English-language articles pub-
(n = 1). Members of the expert panel were selected based on the following criteria: a practic-
lished between 2016 and 2021. For this search, a combination of the following key-
ing obstetrician–gynecologist with more than 15 years of experience; a regionally or nation-
words was used: iron deficiency anemia, pregnancy/pregnant women, non-pregnant
ally recognized
women, expert in obstetricsgirls,
adolescents/adolescent and perimenopause/perimenopausal
gynecology; considerable experience in the diagno-
women, preven-
sis, evaluation, and management of ID/IDA; previous experience as
tion/prophylactic, treatment/therapeutic, iron status assessment/evaluation, serum an advisory board
fer-
ritin/ferritin, TSAT/transferrin saturation, socioeconomic status/factors, cultural sur-
member; and an editorial board member for a reputable regional journal. The Delphi fac-
veys were administered
tors/practices, anonymously to the panel
iron supplementation/therapy, between February
iron dose/dosage, and September
guideline, 2022
and consensus.
using SurveyMonkey
De-duplication of the (www.surveymonkey.co.uk,
search results identified 1763accessed on 2 January
publications. 2022).
Of these, 202 Notably, all
were classi-
panelists were asked to provide feedback based on their perspectives, experience,
fied as relevant based on their titles and abstracts, with 10 additional publications identified and the
latest Google
from literature, with theThe
searches. goal of improving
expert panel hadpractices
access across the Asia-Pacific
to all relevant region.
information and docu-
ments during the Delphi rounds and during the development of this manuscript.
2.2. Development
Tables S1–S4 of (in
ItemstheforSupplementary
Round 1 of the Delphi Surveypresent all statements included in
Materials)
Delphi The statements
Round 1 acrossforfour
Delphi Round identification;
domains: 1 were developed from aand
diagnosis review of the literature.
assessment; The
prevention;
PubMed
and database of
the treatment was searched
ID/IDA for full-text English-language articles published between
in women.
2016 A six-point
and 2021. For Likert
this scale
search,was used for panelists
a combination to rate their
of the following level ofwas
keywords agreement or
used: iron
disagreement
deficiency anemia, withpregnancy/pregnant
each Delphi item: women, stronglynon-pregnant
disagree, disagree,
women,somewhat disagree,
adolescents/adoles-
somewhat
cent girls, agree, agree, and strongly agree. The
perimenopause/perimenopausal Delphiprevention/prophylactic,
women, statements were derived treat- from
published research
ment/therapeutic, and
iron recommendations;
status therefore,
assessment/evaluation, we expected
serum a fairlyTSAT/transfer-
ferritin/ferritin, high level of
agreement and socioeconomic
rin saturation, set an 85% threshold (the sum cultural
status/factors, of agree factors/practices,
and strongly agree) ironforsupplementa-
both Rounds
1tion/therapy,
and 2. A free-text field was included for each statement to allow
iron dose/dosage, guideline, and consensus. De-duplication of the panelists the opportunity
search re-
to explain their responses and propose new statements for Round 2.
sults identified 1763 publications. Of these, 202 were classified as relevant based on their
titles and abstracts, with 10 additional publications identified from Google searches. The
2.3. Development of Items for Round 2 of the Delphi Survey
expert panel had access to all relevant information and documents during the Delphi rounds
The results
and during of Round 1, including
the development free-text comments and feedback, were tabulated to
of this manuscript.
inform Tables S1–S4 (in the Supplementary2Materials)
the development of the Round survey. A present
copy ofall these results was
statements also shared
included in Del-
with panel members in Round 2, as they reconsidered their responses
phi Round 1 across four domains: identification; diagnosis and assessment; prevention; to statements that
did not meet consensus in
and the treatment of ID/IDA in women.Round 1. Similar to Round 1, free-text fields were included in
Round 2 for panelists to justify and elaborate their responses.
A six-point Likert scale was used for panelists to rate their level of agreement or dis-
agreement with each Delphi item: strongly disagree, disagree, somewhat disagree, some-
2.4. Grading of Statements
what agree, agree, and strongly agree. The Delphi statements were derived from pub-
lishedAfter two Delphi
research rounds, the level therefore,
and recommendations; of agreementwe for each statement
expected waslevel
a fairly high graded using
of agree-
a
ment and set an 85% threshold (the sum of agree and strongly agree) for both Rounds A
scale that has previously been described [19]: grade U (100%; unanimous), grade 1
(90–99%; near unanimous),
and 2. A free-text grade B (78–89%;
field was included strong agreement
for each statement with littlethe
to allow panelists variance), and
opportunity
grade C (67–77%;
to explain moderate
their responses andagreement).
propose new Forstatements
this Delphi
forconsensus,
Round 2. the grading system

2.3. Development of Items for Round 2 of the Delphi Survey

The results of Round 1, including free-text comments and feedback, were tabulated
to inform the development of the Round 2 survey. A copy of these results was also shared
Nutrients 2023, 15, 3125 4 of 14

was modified to include grade D (0–66%) to indicate statements that reflected extremely
diverse opinions.

2.5. Development of Clinical Pathway Algorithms

Based on the results of both Delphi rounds, statements were formatted into clinical
pathway algorithms around pre-determined domains (i.e., identification, diagnosis and
assessment, prevention, and treatment of ID/IDA), with graded recommendations assigned
to each decision point.

3. Results
Tables S1–S4 present the results of Delphi Round 1 and Round 2. Table 1 shows the
number of statements retained in each round. In Round 1, experts retained 72 (73%) of the
initial 99 statements. The Delphi Round 2 survey removed two statements and included
16 new additional statements, in which experts retained 95 (84%) of 113 statements. Clinical
pathway algorithms were developed based on key statements retained in the final round.

Table 1. Overview of the Delphi survey results.

No. of Retained Delphi Items, n/N (%)

Domain
Round 1 Round 2
Identification of ID/IDA 22/24 (92%) 26/29 a (90%)
Diagnosis and assessment of ID/IDA 20/37 (54%) 28/35 b (80%)
Prevention of ID/IDA 12/16 (75%) 15/16 (94%)
Treatment of ID/IDA 18/22 (82%) 26/33 c (79%)
Total 72/99 (73%) 95/113 (84%)
aFive new statements were added for inclusion in Round 2. b Two statements that did not reach consensus in
Round 1 were removed. c 11 new statements were added for inclusion in Round 2.

3.1. Identification of ID/IDA in Women

After two Delphi rounds, consensus was reached on the need for the early detection of
ID in all targeted subgroups of women (i.e., pregnant women, non-pregnant adult women,
adolescent girls, and perimenopausal women); however, experts did not identify non-
pregnant adult women and perimenopausal women as ‘high-risk’ subgroups for ID and the
development of IDA. Experts reached a positive consensus on the majority of statements
relating to presenting symptoms and risk factors that should prompt assessment of anemia
and iron status; the statement that remained controversial concerned the significance of
clinical pallor in the detection of ID/IDA in pregnant women.

3.2. Diagnosis and Assessment of ID/IDA in Women

Experts agreed that lower-than-normal serum ferritin is the most specific early marker
for the diagnosis of ID in women. A positive consensus was almost reached (75% agreement)
on serum ferritin being the most effective diagnostic strategy for ID in pregnancy; however,
no consensus was achieved concerning the serum ferritin threshold for the diagnosis of ID
during the first trimester of pregnancy. Importantly, a positive consensus was reached on
the need for serum ferritin testing in anemic women to confirm IDA. No consensus was
reached on the role of serum inflammatory markers, clinical signs, and oral iron therapy
in excluding or supporting a diagnosis of IDA. Figure S1 illustrates the clinical pathway
algorithm for the identification, and diagnosis and assessment of ID/IDA in women.

3.3. Prevention of ID/IDA in Women

All statements concerning the importance of preventing ID/IDA in women reached
a positive consensus in the first Delphi round. Experts agreed that preventive iron sup-
plementation should be recommended for all targeted subgroups of women residing in
settings where screening for ID/IDA is not adequate. In addition, consensus was reached
Nutrients 2023, 15, 3125 5 of 14

on the provision of preventive iron supplementation for pregnant women irrespective of

anemia prevalence levels, and for other targeted subgroups of women living in areas with
a high anemia prevalence. Almost all statements describing oral iron dosing recommenda-
tions for prevention of ID/IDA achieved a positive consensus in Round 2; however, the
optimal oral iron dosing for pregnant women in settings with a low anemia prevalence
remained controversial. The decision tree shown in Figure S2 depicts the clinical pathway
algorithm for the prevention of ID/IDA in women.

3.4. Treatment of ID/IDA in Women

Experts agreed that oral ferrous iron should be recommended as first-line therapy
for all targeted subgroups of women with uncomplicated ID/IDA. Following two Delphi
rounds, consensus was also reached on statements indicating oral iron dosing recom-
mendations for the treatment of mild IDA, as well as those describing situations where
intravenous iron is appropriate. Additional new statements regarding the combination
of multiple micronutrients with oral iron reached a positive consensus. Statements that
remained controversial concerned oral iron dosing recommendations for the treatment of
mild-to-moderate IDA and the state of evidence guiding the optimal therapeutic dosing
for moderate-to-severe ID/IDA in adolescent girls, and for severe IDA in non-pregnant
adult women, adolescent girls, and perimenopausal women. Figure S3 defines the clinical
pathway algorithm for the treatment of ID/IDA in women.

4. Discussion
The overarching purpose of this expert consensus is to provide clinicians practicing
within the Asia-Pacific region with a straightforward set of recommendations that reflect
current practices and can be readily implemented to improve long-term health outcomes
for women at risk or presenting with ID/IDA. Previously published Asia-Pacific regional
expert recommendations were developed to reduce the morbidity and mortality associ-
ated with end-stage IDA in the pregnancy and postpartum phase, and were therefore not
addressing the continuum of prevention to early intervention and treatment [20]. Addi-
tionally, the threshold guidance for the detection of ID/IDA is outdated and not consistent
with the more recent WHO guidelines. In view of this and the widely observed practice
variations in the region, statements generated for this Delphi consensus encompass the
identification, diagnosis and assessment, prevention, and treatment of ID/IDA across key
subgroups of women: pregnant women, non-pregnant adult women, adolescent girls, and
perimenopausal women.

4.1. Identification of ID/IDA in Women

Relative to pregnant women and adolescent females who are widely recognized as
two groups most vulnerable to ID/IDA [21–24], many clinicians do not identify adult
and perimenopausal women as ‘high-risk’ despite the fact that approximately 40% of
non-pregnant women have low iron stores [25]. In addition, many national and interna-
tional guidelines recognize the importance of screening and treating ID/IDA associated
with heavy menstrual bleeding (HMB), which is estimated to affect 18–38% of women of
reproductive age, and is higher among perimenopausal women [26].
Although ID is a leading cause of anemia, ID, IDA, and anemia should not be con-
flated [6,27]. The largest amount of circulating iron (~80%) is used for hemoglobin (Hb)
synthesis; therefore, the absence of anemia is assumed to imply adequate iron stores [9,28].
However, IDA is the result of ID, as Hb synthesis is typically preserved until the advanced
stages of ID [9].
Therefore, ID among women is easily missed, leaving early stages of treatable ID
unidentified and untreated [27]. For this reason, risk factors and presenting symptoms
indicative of ID assume an important role in the diagnostic process, although certain
symptoms of ID do not always manifest until IDA develops. When symptoms are present
in adolescent females with non-anemic ID, they commonly include fatigue, and decreased
Nutrients 2023, 15, 3125 6 of 14

verbal learning and memory [29]. In perimenopausal women, these may include fatigue
and impaired exercise capacity [2]. However, the extent to which these non-hematological
symptoms are manifested before anemia remains unclear, and given the lack of published
evidence to directly inform recommendations, there are no firm pathways to guide their
investigations or monitoring [30,31].
Pallor of the skin, conjunctivae, and nail bed is one of the most recognized signs of
IDA [32,33]. The quantitative assessment of pallor for the diagnosis of anemia remains
an area of active investigation, with a wide range of estimated sensitivities and specifici-
ties [34,35]. Although it cannot be relied on to diagnose IDA, the presence of pallor in
women should prompt the clinician to assess anemia and iron status, and consider the
diagnosis of IDA, especially when its presence is a change from normal in the patient [32,36].
In cases of non-anemic ID, non-hematological symptoms, such as fatigue, can be present
without anemic Hb levels.
HMB is a well-established risk factor for ID/IDA in pregnant and menstruating
females, who often normalize or conceal their bleeding due to negative cultural perceptions
of bleeding [1,2]. In addition to heavy uterine bleeding, multiparity increases the risk
of ID during pregnancy and should always prompt testing and management, if ID/IDA
is suspected [37]. Accordingly, a recent prospective cohort study showed that Hb lower
than 12.0 g/dL in the first trimester of pregnancy was predictive of IDA at the end of
pregnancy [38]. Identified risk factors for ID/IDA post-delivery include postpartum blood
loss (>500 mL), uncorrected anemia detected during pregnancy, and symptoms suggestive
of ID/IDA [33].

4.2. Diagnosis and Assessment of ID/IDA in Women

The WHO defines a diagnostic threshold for ID based on serum ferritin (SF) and
severity threshold for anemia based on Hb [27]. Supported by a low to very low certainty
of evidence, an SF cutoff of <15 µg/L is recommended for otherwise healthy adolescents,
non-pregnant adults, and older adults [27,39]. This cutoff value is increased to <70 µg/L in
the context of inflammation or infection [39]. The WHO also recommends an SF cutoff of
<15 µg/L for pregnant women in their first trimester, but with no thresholds proposed for
the second or third trimester of pregnancy [27,39]. Recent guidance by the British Society
for Haematology (BSH) and the American College of Obstetricians and Gynecologists
proposed a higher threshold of <30 µg/L to indicate ID during pregnancy, based on a 90%
probability that iron stores are depleted when SF falls below 30 µg/L [27].
Determining an optimal threshold based on consensus methods is a significant chal-
lenge because there is no definitive evidence to support any of these recommended cut-
offs [40]. A threshold of <15 µg/L would be deemed to be specific, but will likely miss
many cases of ID [40]. A cutoff of <30 µg/L is highly sensitive, but can lead to more false
positives. In pregnant women, a higher threshold is thought to address the uncertainty of
iron consumption, proinflammatory changes, and the expansion of blood volume during
pregnancy; however, this can result in increased health and economic burden of disease in
countries where prevalence of ID/IDA is already very high [41]. As most Delphi panelists
practice in resource-limited settings, it may come as no surprise that there was a unanimous
consensus to implement an SF cutoff of <15 µg/L for the diagnosis of ID in otherwise
healthy women.
Due to the acute phase nature of SF, serum inflammatory markers, such as ESR and
CRP, are widely used in clinical practice to help interpret ferritin levels [42]. Markedly
elevated ESR and CRP levels should prompt consideration of autoimmune disorders and
chronic infections [42]. The WHO indicates that the concurrent assessment of inflammatory
markers is only necessary in areas at high risk of infection or inflammation [39], which
may explain the lack of consensus in considering inflammatory marker testing among
Delphi panelists.
In most cases, IDA can be effectively diagnosed by assessing Hb and SF [9]. However,
due to the lack of simple and inexpensive point-of-care tests, the practice of using the Hb
Nutrients 2023, 15, 3125 7 of 14

concentration as a proxy for ID/IDA persists in many healthcare settings [27,43]. In anemic
patients with suspected iron depletion states, a low SF provides a definitive diagnosis of
IDA [27,44]. In cases with borderline SF, ID is typically confirmed with a panel of markers
which may include serum iron, total iron-binding capacity, and transferrin saturation [44,45].
Newer iron status parameters, such as soluble transferrin receptors, reticulocyte Hb content,
and serum hepcidin, are promising additions to the panel of diagnostic tests for ID; however,
these assays are not widely available and are not adequately standardized [44].
A diagnosis of IDA in women should also prompt consideration of its cause, partic-
ularly gynecological bleeding [46]. Patients with obvious blood loss (e.g., women with
menorrhagia) would not require an extensive diagnostic workup. In patients with IDA due
to multiple mechanisms (e.g., the elderly, chronic inflammatory conditions, and malnutri-
tion), further diagnostic testing may be necessary to determine its additional causes [47].
The evaluation and treatment of additional causes of IDA can aid in the resolution of IDA
beyond iron therapy [47]. In iron-replete women with anemia, additional diagnostic tests
can help determine the alternate causes of anemia and its appropriate intervention [47]. The
BSH and the British Society of Gastroenterology (BSG) guidelines recommend that in ane-
mic pregnant and non-pregnant adult women at low risk for non-adherence, a therapeutic
trial of oral iron for 2–4 weeks can aid in diagnosing IDA [33,48].

4.3. Prevention of ID/IDA in Women

In the past, anemia prevention strategies for women had focused on preventing
ID/IDA in pregnancy, which remains to be a leading cause of maternal deaths and adverse
pregnancy outcomes in developing regions [49]. Additionally, it has been well established
that women suffer from all consequences of ID/IDA whether or not they are pregnant. ID in
non-pregnant women has been associated with reduced endurance and work performance,
impaired intellectual and cognitive functions, and depression [50]. In addition, irritability,
decreased endurance, and withdrawal behavior may be observed among women with mild
ID [51].
Given its profound impact on aerobic and endurance capacity, IDA can result in
reduced physical performance and work tolerance [50]. In addition to work productivity
and voluntary activity, both ID and IDA have a clinically significant effect on fatigue
and athletic performance in women [50]. Furthermore, iron adequacy during pregnancy
can only be assured when the woman enters pregnancy with optimal iron reserves [52].
Therefore, clinicians should strive to prevent and treat even mild ID among adolescent
females and non-pregnant adult women.
Extensive evidence supports the efficacy and safety of oral iron for the prevention and
treatment of ID/IDA in both pregnant and non-pregnant women [7,53–57]. Current WHO
guidance for the prevention of ID/IDA in women recommends daily supplementation
of oral iron for 3 consecutive months in a year to all non-pregnant adult women and
adolescent girls in countries with an anemia prevalence greater than 40% (i.e., 47% among
reproductive-age and non-pregnant women in the WHO Southeast Asia Region [58,59])
and intermittent supplementation in settings with lower prevalence [12,24].
In pregnant women, the WHO advocates daily supplementation of oral iron and
folic acid in settings where at least 40% of pregnant women are anemic (i.e., 48% among
pregnant women in the WHO Southeast Asia Region [60]), and weekly intermittent doses
where the prevalence is lower than 20%, and if oral iron is poorly tolerated [23]. This is
consistent with the view that enterocytes become refractive to absorbing additional iron
until they are replaced by new enterocytes after 5–6 days and, as such, the provision of iron
doses at weekly intervals is expected to increase absorption and reduce gastrointestinal (GI)
exposure to unabsorbed elemental iron [61]. In addition, the data show a 35% reduction in
the incidence of anemia without an increased risk of GI adverse events [62].
Although the risks and benefits of preventive oral iron during pregnancy have been
debated [38,63], experts in current Delphi consensus support the use of preventive oral iron
Nutrients 2023, 15, 3125 8 of 14

in all targeted subgroups of women, including pregnant women, who reside in developing
regions where access to ID/IDA screening is limited [7,63].

4.4. Treatment of ID/IDA in Women

The treatment of IDA should aim to replete iron stores and restore normal Hb lev-
els [64]. Many expert groups and clinical guidelines recommend oral iron as first-line
therapy for the treatment of uncomplicated ID/IDA in women [48,65–67]. As ferrous
iron is more bioavailable and effective at restoring Hb levels compared with ferric iron,
oral ferrous iron remains the standard treatment option for ID/IDA [67,68]. The three
most widely used oral ferrous iron preparations are ferrous sulfate, ferrous gluconate, and
ferrous fumarate (Table 2) [48,68,69].

Table 2. Oral ferrous iron.

Formulation Preparation Dose (mg) * Elemental Iron (mg) *

Ferrous fumarate Tablet 325 106
Ferrous gluconate Tablet 325 35
Ferrous sulphate Tablet 325 65
* Values are based on Govindappagari, S, et al. [70].

In an effort to ensure a positive pregnancy experience for women, the WHO recom-
mends increasing daily elemental iron from the standard daily antenatal dose of 30–60 mg
to 120 mg for pregnant and postpartum women diagnosed with IDA, until Hb levels are
normalized [23,71]. For non-pregnant adult women and adolescent girls with ID/IDA, clin-
icians are advised to follow national guidelines [24]; however, there is little published evi-
dence and consensus on the recommended dose and dosing frequency of oral iron [23,67,72],
resulting in inconsistencies in care and patient outcomes.
Although oral ferrous iron is conventionally dosed at 100–200 mg per day, given as
three or four divided doses, experts in the present Delphi consensus agreed with the evolv-
ing evidence base that changing from consecutive-day to alternate-day schedules [61,73]
and from divided to single morning doses [73] may optimize iron absorption and improve
tolerability. Stoffel and colleagues found that single morning doses of 60–120 mg oral
elemental iron plus ascorbic acid (i.e., a potent enhancer of iron absorption) on alternate
days resulted in improved fractional iron absorption and may be the optimal oral dosing
regimen for women with ID and mild IDA [61,67]. A single morning dose of oral iron
augments plasma hepcidin, a negative regulator of systemic iron homeostasis. In view of
the circadian increase in hepcidin over the day and to ensure that elevated hepcidin does
not reach levels that would inhibit iron absorption, iron doses given in the afternoon or
evening after a morning dose are not recommended [67,74].
There is a notion that patients who are given less frequent dosing may experience
lower Hb increases, and thus may require longer durations of treatment [75]. Kaundal and
colleagues demonstrated that while the median increase in Hb levels was faster in patients
given two divided doses (i.e., 60 mg elemental iron BID) on consecutive days vs. single
doses (i.e., 120 mg elemental iron QD) on alternate days, the difference in Hb levels as well
as the total amount of iron was not observed at subsequent few weeks of treatment [76].
Although increasing evidence indicates similar or improved clinical response with
alternate-day dosing [65,74], daily dosing of oral iron has maintained its role as a go-to
treatment approach in many countries worldwide. In fact, recently published data from a
large randomized controlled trial in India revealed that in 200 adults with IDA treated with
either alternate-day or daily oral iron, there were no clinically meaningful differences in
Hb improvement or safety outcomes between the two treatment arms [77].
However, the decision to prescribe alternate-day or consecutive-day oral iron therapy
should depend on the severity of ID/IDA and patient preference (i.e., the desired rate
of Hb response and tolerance to oral iron). If the rate of Hb response is not important
Nutrients 2023, 15, 3125 9 of 14

but tolerance is, which is the case in mild IDA, alternate-day supplementation should be
considered. In cases of moderate IDA requiring a rapid Hb response, consecutive-day
supplementation remains a pertinent option, which may explain the high level of consensus
achieved in the current Delphi consensus for statements relating to the role of daily oral
iron in the treatment of women with mild to moderate IDA. After the correction of Hb, oral
iron treatment should be continued for at least 3 months, and in clinical practice, it may be
preferable to discontinue oral iron once normal SF levels are restored [7,67,78].
In addition to alternate-day dosing, adherence might improve with lower iron doses
or selecting ferrous gluconate [75,79]. Notably, recent BSH guidelines recommend a lower
range of 40–80 mg oral elemental iron every morning for the treatment of mild IDA. Addi-
tionally, newer iron formulations, such as sucrosomial iron, have a lower dose requirement
compared with commonly available iron supplements [80]. While recent guidelines, in-
cluding the BSH and BSG, recommend ferrous fumarate, sulphate, or gluconate for the
treatment of ID/IDA, data from a systematic review assessing the tolerability of different
oral iron formulations suggest improved adherence with ferrous gluconate or sulfate vs.
ferrous fumarate [33,48,81]. Importantly, in clinical practice, it may be preferable to discuss
with the patient to determine the optimal oral iron dosing, frequency, and duration, with
the goal of optimizing efficacy and adherence [74].
In addition to iron, vitamin B12, folic acid, copper, and zinc are essential micronu-
trients for the synthesis of Hb [82]. Deficiency in any of these micronutrients can lead to
anemia. Single micronutrient deficiencies (MNDs) rarely occur in humans [82,83], and
MNDs are known to co-exist and interact. In patients with anemia, ID is more likely to be
associated with other multiple MNDs [83,84]. Therefore, multiple-micronutrient (MMN)
supplementation has been suggested to be more effective than iron alone in reducing
anemia [83,84]. A Cochrane review provides compelling evidence that oral MMN supple-
mentation during pregnancy is associated with improved birth outcomes (i.e., reduced
risk of small-for-gestational age, low birthweight, and stillbirths) compared with oral iron
(with or without folic acid), with no important benefit or harm on mortality outcomes [84].
Based on the latest evidence and considerations, the 2020 WHO guidance on antenatal care
recommends oral MMN supplementation in settings where implementation research has
been conducted to establish the positive impact of switching from oral iron–folic acid to
MMN supplementation [85]. Furthermore, experts on this Delphi panel considered oral
MMN supplementation to be a rational approach to treating ID/IDA in women.
As the stability and safety of modern formulations are better recognized, the use
of intravenous iron for the treatment of ID/IDA has increased considerably [1,86]. Oral
iron remains the cornerstone of treatment of ID/IDA in women; however, in some cases,
intravenous iron is required. Intravenous iron is typically reserved for patients with severe
ID/IDA and in whom oral iron is not well tolerated [26,67,87]. In addition, intravenous iron
may be preferred when the rapid correction of ID/IDA is required [87]. A meta-analysis of
randomized controlled trials found that while intravenous iron was more effective than
oral iron in improving maternal hematological outcomes in pregnant women with IDA, the
effects on neonatal hematological parameters were similar across treatment arms [88]. In a
more recent clinical trial, reductions in adverse maternal and fetal outcomes were found to
be similar for intravenous vs. oral iron [89]. The lack of differences in clinical outcomes
vs. oral iron does not support the use of intravenous iron in preference to oral iron as the
first-line treatment of ID/IDA in pregnant women [88]. Experts on the current Delphi panel
concurred with the BSH guidelines which recommend intravenous iron from the second
trimester onwards for pregnant women with IDA who cannot tolerate or do not respond to
oral iron, and when a rapid correction of IDA is required [33]. Based on the best available
evidence, experts also recommended intravenous iron in non-pregnant adult women,
adolescent girls, and perimenopausal women in whom the severity of ID/IDA requires
prompt management [90–92]. However, given the cost required for its implementation,
many women in resource-limited settings still do not have access to needed intravenous
iron [1].
Nutrients 2023, 15, 3125 10 of 14

4.5. Strengths and Limitations

This Delphi consensus featured several strengths. The resulting statements for which
consensus was achieved reflect the views of experts with relevant expertise and experience
in preventing and managing women with ID/IDA in the Asia-Pacific region. Although
generated through a consensus process, these statements were derived from the medical
literature and existing guidelines, and are therefore evidence-based. In addition, the
high consensus threshold ensured that the recommendations were unequivocal. A few
limitations should be noted. The size of the expert panel may not be representative
of all Asia-Pacific countries, and therefore not generalizable to women outside of the
represented countries with differing cultures and values, healthcare access, and quality of
care received. For example, pregnant women in developing countries of low socioeconomic
status, such as India, are less likely to receive timely iron status assessment or adhere to
iron supplementation [93,94]. Secondly, the absence of online or in-person meetings after
each Delphi round may have deprived panelists from exchanging pertinent information
and clarifying reasons for disagreement. Additionally, it is acknowledged that the majority
of statements were not supported by Level 1 studies; however, it is unlikely that large well-
designed randomized controlled trials relating to the recognition, diagnosis, assessment,
prevention, and treatment of ID/IDA in women will be published in the near future.

5. Conclusions
Within the Asia-Pacific region, obstetrician–gynecologists have a critical role to play in
the identification, diagnosis, and management of ID/IDA. The primary focus should be on
women at risk or presenting with ID/IDA. Consensus was also reached for 95 statements
representing four domains (i.e., identification; diagnosis and assessment; prevention; and
treatment of ID/IDA in women) that could be used to aid clinical decision-making for
women presenting to the obstetrics and gynecology clinic and should not be interpreted
as the only course of management. Key areas of consensus were around the identifica-
tion and prevention of ID/IDA. There was a lack of consensus on statements relating
to oral iron treatment of mild-to-moderate ID/IDA in women. In practice, patient in-
volvement in shared decision-making around iron supplementation is key to improving
adherence and clinical outcomes. Importantly, these consensus statements may serve as
a pertinent step to standardizing the care of women at risk or with ID/IDA, and should
be periodically reviewed to ensure consistency with the current medical literature and
international guidelines.

Supplementary Materials: The following supporting information can be downloaded at:

https://www.mdpi.com/article/10.3390/nu15143125/s1, Figure S1: Clinical pathway algorithm for
the identification, and diagnosis and assessment of ID/IDA in women; Figure S2: Clinical pathway
algorithm for the prevention of ID/IDA in women; Figure S3: Clinical pathway algorithm for the
treatment of ID/IDA in women; Table S1: Delphi results for statements relating to the identification
of women at risk for ID/IDA; Table S2: Delphi results for statements relating to the diagnosis and
assessment of ID/IDA in women; Table S3: Delphi results for statements relating to the prevention
of ID/IDA in women; Table S4: Delphi results for statements relating to the treatment of ID/IDA
in women.
Author Contributions: R.D.P., Y.S.C., L.R.C.-C., R.I., T.N.K.H., N.W., M.C.Z.G. and Z.A.M. con-
tributed to the concept and design of this consensus document. The manuscript draft was developed
and critically reviewed by all the authors. All authors have read and agreed to the published version
of the manuscript.
Funding: Procter & Gamble Health.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Nutrients 2023, 15, 3125 11 of 14

Acknowledgments: We acknowledge Mediwrite Asia Inc. Pte Ltd., Singapore for the medical
writing support.
Conflicts of Interest: The expert panel consensus meeting was organized in association with Procter
& Gamble Health. We acknowledge Jass Liew and Vinod Malve, employees of Procter & Gamble
Health, for organizing the logistics of the consensus meeting.

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