DOI: 10.1002/ijgo.

14944

SUPPLEMENT ARTICLE

Iron deficiency, pregnancy, and neonatal development

Ricardo Ataide1,2 | Katherine Fielding1 | Sant-­Rayn Pasricha1,3,4,5 | Cavan Bennett1,3

1
Population Health and Immunity Division,
The Walter and Eliza Hall Institute, Abstract
Melbourne, Australia
Anemia affects 36% of pregnant women worldwide. Of those affected, around 40% is
2
Department of Infectious Diseases, The
Peter Doherty Institute for Infection and
due to iron deficiency (ID). Iron is an essential micronutrient involved in vital processes
Immunity, Melbourne, Australia such as erythropoiesis, immune responses, and importantly—­
during pregnancy—­
3
Department of Medical Biology, The placental and fetal development. Although menstrual bleeding can impact the inci-
University of Melbourne, Melbourne,
Australia dence of ID even before the onset of pregnancy, this narrative review is pregnancy
4
Diagnostic Hematology, The Royal focused and will explore the impact of ID on placental development and iron uptake,
Melbourne Hospital, Parkville, Australia
5
fetal development and immunity, and maternal and infant susceptibility to infection.
Clinical Hematology at the Royal
Melbourne Hospital and Peter MacCallum Although there have been advances in this area of research, much is needed to un-
Cancer Centre, Parkville, Australia derstand the regulation of iron and the effects of ID during pregnancy. Notably, more
Correspondence human studies are essential to generate the best evidence to advance strategies to
Ricardo Ataide, The Walter and Eliza reduce the incidence of ID during pregnancy to improve maternal, neonatal, and in-
Hall Institute, 1G Royal Parade, Parkville,
Melbourne, Victoria 3052, Australia. fant health.
Email: ataide.r@wehi.edu.au
KEYWORDS
anemia, growth, infection, iron, iron deficiency, neonate, placenta, pregnancy

1 | I NTRO D U C TI O N development.9 Although approaches to preventing anemia and ID

Although there have been slight reductions in the prevalence of ane-
mia in pregnant women, the latest estimates indicate that globally
36% of all pregnant women aged 15–­49 years still experience anemia
(this value ranges from a mean of 17.2% [12.7–­22.8] in high-­income
1,2
countries to 42.6% [39.1–­46.0] in low-­income countries). The most
common causes of anemia are related to inherited red blood cell disor-
ders, infections (such as malaria and intestinal helminths), inflammatory
diseases, and nutrient deficiencies.1,3 Iron deficiency (ID) is estimated
to contribute to 40% of worldwide anemias during pregnancy.4 Iron is
required for the expanded erythropoiesis that occurs, along with the
plasma volume increase that occurs in the second and third trimesters,5
6
and for the development of the placenta and fetus. Maternal anemia
may lead to life-­threatening complications for both mother and baby,7
with long-­lasting complications such as low birth weight8 and low iron
stores in infancy, possibly leading to childhood anemia and impaired
before pregnancy (e.g. by addressing menstrual bleeding as a source
of anemia and iron loss10) are being considered, mother and child are
often the main subjects of studies and interventions, with a growing
interest in studying the effects of anemia, particularly ID, on the pla-
centa.6,11–­14 This is because the placenta, as a constantly developing
organ, must balance its own iron needs with those of the mother and
fetus and could be seen as a central player in iron availability during
pregnancy.6 Hence, we sought to evaluate the extent of the effect of ID
during pregnancy on the placenta, the fetus, and the newborn.
2 | S CO PE
In this narrative review we summarize the evidence for the ef-
fect of ID on the placenta, the fetus, and the newborn/infant. We
searched PubMed and Scopus for articles using “iron deficiency” and

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology
and Obstetrics.

14 | 
wileyonlinelibrary.com/journal/ijgo Int J Gynecol Obstet. 2023;162(Suppl. 2):14–22.
ATAIDE et al.
“pregnancy” as keywords together with “placenta,” “growth,” “birth
weight,” “immunity,” “infection,” “vaccine,” and “antibody.” We iden-
tified suitable references via abstract selection and subsequent full-­
text revision. Our focus was on primary works from the last 10 years,
with recourse literature reviews from the past 20 years where
knowledge data have not progressed recently. We included reports
and publications from international organizations and applied the
“snowball” method, finding new references within selected studies.
We discuss three primary areas of interest: (1) Placental develop-
ment and iron uptake: this research area has increased significantly in
recent years. The understanding of how the placenta regulates its iron
requirements when it senses maternal ID and how it then manages
fetal iron requirements is still in its infancy. Some of the receptors
involved in this process, as well as some of the placental outcomes,
have been described, but much remains to be understood6,12,14–­19; (2)
Fetal growth and immunity: iron supplements and treatments during
pregnancy seem to decrease the incidence of low birthweight babies8;
however, a complete understanding of how ID contributes to reduced
birth weight is still the subject of several studies. Another important
area of research concerns iron's essential role in immune development
and function.20,21 Iron deficiency may impact infant responses to vac-
cination, 22,23 but how prenatal ID or iron stores at birth influence in-
fant vaccine responses is not known. We did not address the impacts
of iron on neurodevelopment since this is the subject of another re-
24
view in this Supplement ; (3) Maternal and infant susceptibility to
infections: infections may influence iron metabolism, for example, via
upregulation of hepcidin, via direct effects on ferroportin expression,
and upregulation of ferritin expression. However, the impact of ID on
infection is less often studied.25–­30
We need to understand the intricacies of ID during pregnancy:
whom it affects, at what pregnancy stage, and its outcomes. This
knowledge will provide the necessary evidence to push forward,
with renewed vigor, strategies to reduce the incidence of ID during
pregnancy, potentially prevent pregnancy complications, and im-
prove neonatal and infant health.
3 | I RO N PH YS I O LO G Y: A S U M M A RY
Iron is a critical trace element that in humans is contained in proteins
that carry oxygen (hemoglobin) and enzymes that catalyze essen-
tial reactions (e.g. cytochromes and myeloperoxidase). The average
adult contains 3–­4 g of iron, with approximately two-­thirds of the
iron in the erythroid compartment.31,32 The remaining iron is stored
bound to ferritin in the peripheral organs, mainly in the liver. Iron
within the plasma (i.e. iron available to supply cellular needs) is nearly
all bound to circulating transferrin and has a high turnover, with ap-
proximately 25 mg of iron entering and exiting the plasma daily.32
The plasma also contains ferritin, with plasma ferritin levels correlat-
ing to body iron levels; although increases in circulating ferritin in the
33
context of infection make it a less-­than-­ideal marker.
A small amount (1–­2 mg/day) of dietary iron enters the plasma
via duodenal enterocytes (Figure 1). Nonheme iron enters the
| 15
enterocytes via divalent metal transporter 1 (DMT1)34 on the apical
membrane. It exits into the plasma via the only known iron exporter,
ferroportin (FPN), on the basolateral membrane. The mechanism by
which heme-­bound iron enters the duodenal enterocytes is still not
fully understood. Most iron entering the plasma (about 25 mg/day) is
supplied by releasing iron recycled from senescent red cells by splenic
macrophages. Iron entry to the plasma is controlled by the master reg-
ulator of iron—­hepatic-­derived hepcidin. Hepcidin binds to, occludes,
and causes the internalization and degradation of FPN, limiting cel-
lular iron export.35–­37 Hepcidin levels are controlled at the transcrip-
tional level through the competing signals of iron status, degree of
erythropoiesis, inflammation, and (possibly) pregnancy status.38,39
As with most of the processes during pregnancy, iron physiology is
modified to suit the needs of a growing fetus. Notably, there is a signif-
icant drop in the levels of maternal hepcidin, allowing for an increase
in iron access to the placenta via enhanced iron absorption and utiliza-
tion, which could support the development and growth of the placen-
ta.39–­42 The trigger for this reduction in hepcidin is still unknown. There
is a strong correlation between the timing of this reduction in hepcidin
and the rapid development and growth of the placenta occurring from
the beginning of the second trimester onward.14,39,40,43 However, as is
the case throughout this review, there is a lack of well-­designed and
sufficiently powered studies in humans to examine how maternal hep-
cidin levels vary during pregnancy with respect to ID.39,44
4 | M ATE R N A L I RO N D E FI C I E N C Y A N D
TH E PL AC E NTA
The placenta mediates all crosstalk between mother and fetus. It
provides the fetus with all the maternal nutrients, metabolites, im-
munoglobulins, and oxygen; it produces hormones necessary for
fetal development and removes fetal waste and carbon dioxide, all
of this while allowing the maternal immune system to tolerate the
growing fetal tissues.45,46 All the iron the fetus receives is removed
from the maternal circulation by the placenta and passed on; how-
ever, the placenta is thrifty and judges the fetus' needs against its
own needs before delivering the cargo.6,14 As will be summarized
below, more research is needed to understand the effect of ID on
the placenta, particularly in human systems.
4.1 | Placental size and weight
Although iron is considered an essential component for placental
development, there is little evidence of an adverse effect of ma-
ternal ID on placental size and weight. Most animal models of diet-­
induced ID have found that placental weight and diameter do not
significantly differ between iron-­deficient animals or animals with
an adequate iron intake.14,47 However, one study of dietary-­iron-­
restricted rats found that, although maternal iron restriction had no
effect on placental weight at gestational day 13.5—­the equivalent of
a human second trimester—­it did result in a 10% increase in placental
16 | ATAIDE et al.

F I G U R E 1 Summary of key aspects of iron availability and hepcidin regulation. Dietary iron enters the circulation via duodenal
enterocytes. Fe3+ is reduced and transported via DMT1 to the cytoplasm, where it gets exported to the circulation via the only iron exporter
identified so far, FPN. This comprises a small proportion of the total iron made available to the circulation (mainly in the form of diferric Tf).
The majority of circulating iron derives from the recycling of senescent red blood cells by splenic macrophages. Increasing levels of iron
promote the upregulation of hepcidin in the liver. Hepcidin is the master iron regulator and promotes the degradation of FPN, thus limiting
the availability of circulating iron. Hepcidin levels can also increase in response to infection/inflammation. During pregnancy, an increase in
the demand for iron depletes iron stores and circulating iron. This is balanced by a reduction in the levels of hepcidin (triggered by a possible
placental factor) that allows for increased iron absorption and, subsequently, iron access to the placenta and the developing fetus. TfR1 on
the surface of the placental syncytiotrophoblast layer facilitates iron transport to the placenta. The diferric Tf:TfR1 complex is internalized,
and iron is transported out of the endosome by DMT1. FPN, situated on the basal side of the syncytiotrophoblast, transports iron out into
the placental stroma. Iron's transport from there to the fetal circulation needs further elucidation.

weight at term and that this effect was mainly seen via an expansion
in the junctional zone of the placenta.43 We did not find convinc-
ing evidence of human studies supporting these results, with only
a small cross-­sectional study of women delivering healthy term ba-
bies seeming to show a nonsignificant decrease in weight between
placentas from women with low serum ferritin (n = 26; mean ferritin
7.65 ± 1.28 μg/L; placental weight 0.59 ± 0.13 kg) versus those with
normal serum ferritin (n = 18; mean ferritin 34.2 ± 12.8 μg/L; placen-
tal weight 0.65 ± 0.21 kg).48
4.2 | Placental iron content
The effect of maternal iron status on placental iron concentration is
also unclear. To a certain extent, placentas maintain a constant level
of nonheme iron independently of maternal or fetal iron status, sug-
gesting that there is a level of placental control of fetal iron endow-
ment and, thus, a self-­regulatory mechanism.13,14 Some studies have
found no difference between iron-­deficient versus iron-­adequate
mice.13 In contrast, others have shown an apparent and gestational-­
age-­dependent decrease in nonheme iron content in placentas from
iron-­deficient mice versus those who were iron replete.14
However, few human studies have examined iron content in
the placentas of iron-­
deficient versus iron-­
adequate mothers.
Those looking at this parameter used different collection methods
and iron content analysis assays and were small and observational.
In women delivering healthy term babies, both the placental non-
heme iron concentration (47.3 ± 24.7 μg/g, n = 26 vs. 39.8 ± 17.7 μg/g,
n = 18) and the total placental nonheme iron (31.2 ± 17.5 mg, n = 26
vs. 27.0 ± 15.3 mg, n = 18) were higher in women with low versus
ATAIDE et al.
those with high ferritin.48 Interestingly, another study of 39 women
using 10 ng/mL of maternal serum ferritin as a cut-­off did not de-
tect any difference between groups concerning placental iron levels
(P = 0.533).14 Collectively, there are inadequate data from human
studies to draw conclusions on the impact of maternal iron status on
placental iron levels.
4.3 | Placental iron transport
As the iron needs for both placental and fetal development vary
according to gestational age, the impact of ID on the regulation of
placental iron transport could plausibly also vary according to the
gestational age at which that ID was experienced. Iron transport
in the placenta has recently been reviewed.6,13,15,40 Importantly, in
human placentas, the outer layer of the syncytiotrophoblast (SCT)—­
the apical side facing the maternal blood—­expresses high levels of
transferrin receptor (TFRC), responsible for bringing nonheme iron
(mainly in the form of diferric transferrin) into the fetal tissues (the
role of nontransferrin-­bound iron, heme iron or ferritin is still under-
studied40,43), while the inner layer—­the basal side facing the placental
stroma—­expresses ferroportin (FPN), responsible for exporting iron
out of the SCT.6,15,19,40 With the understanding that several other
proteins work in tandem to carry iron inside the cell between trans-
porters,6,40 we will focus on iron's entry and exit points. Additionally,
it is vital to keep in mind that iron transport is unidirectional from the
mother to the fetus.
Placental TFRC and FPN see their transcription and protein ex-
pression increase throughout pregnancy and peak near term.13,14
Recent efforts to dissect the effect of maternal iron deficiency on
the levels of these two receptors highlight the difficulties of study-
ing placental mechanisms. In animal models, the levels of TFRC were
seen to increase moderately in the placentas of iron-­deficient mice
14,49
relative to iron-­replete mice. This increase was more pronounced
50
in the placentas of iron-­deficient rats. At the transcriptional level,
in a study that looked at gene expression between iron-­deficient and
iron-­adequate mice by reverse transcription polymerase chain reac-
tion (RT-­PCR) and RNA sequencing, placental TFRC transcript levels
were seen to increase during pregnancy, peak at term, and to be ele-
13
vated in the placentas of dams on an iron-­deficient diet. However,
a different study reported no changes in the transcript levels of TFRC
in the placentas of iron-­deficient rats.50 Regarding ferroportin, stud-
ies in mice show that maternal ID increases FPN expression in pla-
centas from iron-­deficient mice.14,49
In humans, in a small cohort of women with less than 10 ng/
mL of ferritin versus women with more than 10 ng/mL of ferritin,
there were no significant changes to TFRC transcriptional levels, but
there was a slight but significant increase in the level of transferrin
receptor protein 1 (TfR1).14 This study also showed no difference in
FPN levels in the placentas from women with less than 10 ng/mL of
ferritin.14 This confusing picture is made somewhat more apparent
by looking at the ratio between FPN and TRFC protein levels—­a so-­
called placental iron deficiency index (PIDI), which seems to correlate
| 17
better with ID in both mice and human placentas.14 However, vali-
dation studies are required to confirm these observations. Likewise,
DMT1, encoded by SLC11A2, was seen to have increased transcrip-
tion in placentas from iron-­deficient versus iron-­sufficient rats (1.5-­
fold increase, P = 0.01)50 and iron-­deficient placentas from mice.13
At the same time, the protein levels seem not to change between
iron-­replete and iron-­sufficient placentas in rats or mice.49,50 Post-­
transcriptional regulation—­via iron regulatory proteins (IRP) binding
to iron-­responsive elements (IRE) within hairpin structures in target
mRNAs—­plays an essential role in the cellular responses to ID,51,52
and may explain the differences observed between transcriptional
and protein levels of key iron markers. In human placentas, this sys-
tem is active within the SCT and can regulate iron intake.16
4.4 | General placental
transcriptome and proteome
Apart from those directly involved in iron transport, several other
genes and pathways are differentially expressed in iron-­deficient
versus iron-­adequate/replete placentas, indicating that the effects
of iron deficiency go beyond the immediate impact on iron-­related
genes and proteins. However, the various models and methods used
make it difficult to make definitive statements. A study of transcrip-
tional and proteomic changes in iron-­deficient mice found that 244
genes, mapped to biological processes such as myeloid and erythro-
cyte cell differentiation, were differentially regulated in comparison
to placentas from iron-­adequate pregnancies and that about 700
placental proteins, as measured by tandem mass tag mass spec-
trometry, were differentially expressed.13 Only 4% of the genes and
proteins found to be differentially expressed in iron-­deficient pla-
centas—­by RNA sequencing and mass spectrometry—­showed coor-
dinated regulation between the transcriptional and the translational
steps.13 In contrast, in a study done using dietary-­iron-­restricted rats,
there were 464 differently expressed genes between iron-­deficient
and iron-­replete pregnancies, with biological processes such as im-
munomodulation, extracellular matrix remodeling, and nutrient and
hormone transport among the transcripts with the most significant
fold changes.50
5 | M ATE R N A L I RO N D E FI C I E N C Y A N D
I M PAC T S O N N EO N ATA L A N D I N FA NT
H E A LTH
5.1 | Neonatal growth
A baby's birth weight is an important determinant of growth, health,
and survival.53 In animal studies, where diet, infection, and iron
stores can be well accounted for, maternal iron deficiency results
in smaller offspring.50,54,55 Diet-­
induced iron-­
deficient Sprague–­
Dawley dams produced fetuses 13% lighter by the end of gestation
than those from iron-­replete dams.50 A different strain of rats on
18 | ATAIDE et al.
an iron-­deficient diet also had lighter pups at birth compared with
dams on a control diet, with that weight difference carrying through
to 10 days postnatal.54 Similarly, female C57Bl/6 mice on an iron-­
deficient diet had fetuses weighing 30% less than those from dams
on an iron-­adequate or replete diet.56
Several human studies agree with these animal model observa-
tions. A well-­controlled randomized controlled trial for the effect of
iron supplementation during pregnancy on Plasmodium spp infection
found that not only did iron supplementation (daily oral iron tablets)
increase baby weight at delivery by 150 g (95% CI, 56–­244), but that
effect was larger in women with a baseline iron deficiency (measured
as <15 mg/L ferritin) than in those who were iron replete (234 g vs.
39 g; difference 195 g; 95% CI, −3 to 393; P = 0.05).57 Although there
was no mention of controlling for gestational age, one study found
the weight of babies born to women with iron deficiency anemia (IDA)
to be decreased versus control women (2.5 ± 0.3 kg vs. 3.3 ± 0.4 kg,
respectively).58 In a cohort of Iranian pregnant women recruited at
term and without a history of anemia during pregnancy, mothers with
ferritin concentrations between 15 and 49.9 mg/L gave birth to babies
who were heavier than those from mothers with less than 15 mg/L
59
of ferritin (3031 ± 534 g vs. 2467 ± 350 g). Interestingly, women with
even higher ferritin levels (above 50 mg/L) gave birth to even heavier
babies.59 Similarly, women with low ferritin levels (<62 μg/L –­trying to
account for the sensitivity of ferritin to inflammation) but without de-
pleted iron stores (serum ferritin ≥12 μg/L) had babies who were 148 g
(95% CI, 0.5–­296) heavier than those who had depleted iron stores
60
(serum ferritin <12 μg/L). This effect was observed in another study
where birth weight was increased in babies whose mothers had taken
iron supplements, but only when those mothers had low iron status
61
prepregnancy or very early in pregnancy.
Unfortunately, prepregnancy iron stores, the duration of preg-
nancy under low iron stores, the presence and timing of iron sup-
plementation, and the presence of infections can all contribute to
confounding, and so, not all human studies agree with a lower birth
weight in babies born to iron-­deficient mothers. When compared
with mothers in the highest quartile of serum ferritin (Quartile 4:
24.9–­350 ng/mL with no adjustment made to account for inflamma-
tion), those in the two lowest quartiles (Quartile 2: 8.6–­14.7 ng/mL;
62
Quartile 1: <8.6 ng/mL) gave birth to higher birthweight babies.
This finding is somewhat supported by two prospective cohort stud-
ies where lower serum ferritin levels were associated with higher
birth weights.63,64 A study looking specifically at women who were
iron deficient versus those who were not measured maternal plasma
ferritin at 30 weeks of gestation and determined that the newborns
of women in the highest tertile of plasma ferritin (median 29 mg/L)
had, on average, a 93-­g lower birth weight (95% CI, −172 to −14 g,
P = 0.021) than those born to women in the lowest tertile of plasma
ferritin levels (median 8 mg/L).64 Notably, the authors stated that
only a small percentage of women in the study (4%) had any evi-
dence of inflammation, as measured by C-­reactive protein (CRP).64
A randomized controlled trial evaluated the impact of intravenous
iron infusion compared with oral iron supplementation, in women
with moderate anemia in the second trimester of pregnancy in
Malawi (n = 862). There was no significant change in birthweight
observed in those treated with ferric carboxymaltose, despite this
group demonstrating clearly increased ferritin and reduced ID at 36
weeks. Additionally, in subgroup analyses of those with ID or IDA
at baseline, no change in birthweight was seen.65 In a population of
well-­nourished pregnant women, when the percentage of hypochro-
mic red blood cells (%HYPO) was used as a marker of ID, rather than
ferritin, the highest quartile of %HYPO—­indicating iron-­deficient
erythropoiesis—­
was associated with higher baby and placental
weights,66 indicating a beneficial effect of ID.
Defining a role for antenatal iron status on infant growth and
neurodevelopment is especially critical as iron supplementa-
tion in infants was recently shown to be of limited value on these
outcomes.67
5.2 | Infant immunity
A healthy immune system is crucial for an infant. Iron has con-
sistently been associated with a healthy immune system. 68–­70 A
recent study using animal models, as well as samples from patients
with iron refractory IDA—­a condition that renders patients with
elevated levels of hepcidin and thus low iron—­showed how low
serum iron was associated with impaired primary and memory
B-­
cell responses, lower antibody levels against several patho-
gens, and impaired T-­cell responses.71 Iron's role during the gen-
eration and maintenance of an infant's immune system has also
received recent attention. 23,72 Data from a Kenyan birth cohort
where infants were followed up to 18 months of life revealed that
anemia and serum transferrin receptor at the time of vaccination
were the strongest predictors of seroconversion after diphtheria
and pneumococcus serotype 19 vaccination. 23 In line with this,
when following up a cohort from a randomized controlled trial of
iron supplementation (mean age at the start of intervention was
7.5 months; final number of children included in the analyses = 88),
children who received the intervention were found to have higher
anti-­m easles serum immunoglobulin G, a higher seroconversion
rate, and higher antibody avidity. 23 A small case–­control study
of 40 children with IDA versus 20 age-­matched healthy controls
showed that patients had lower levels of total immunoglobulin
G and lowered phagocytic activity than controls.72 What is still
unknown is how much the maternal iron status during pregnancy
contributes to these responses. There are limited data evaluating
perinatal iron status longitudinally and the correlation with the de-
velopment of immunity during infancy, with most studies focusing
on general nutrition. 22,73–­76 Indeed, no randomized controlled tri-
als have evaluated this question.
5.3 | Infant iron status
When trying to correlate maternal and infant iron levels, the choice
of a biomarker for iron level and time point for determining iron
ATAIDE et al.
status is inconsistent such that it is hard to draw clear conclusions.
Mouse models indicate that prenatal iron deficiency results in pups
with lower iron stores. In the absence of inflammation, a mouse
model of ID showed that embryos from dams on an iron-­deficient
diet had significantly lower fetal serum iron, fetal liver nonheme
14
iron, and hemoglobin than those on an iron-­replete diet. A study
conducted using dietary-­iron-­restricted rhesus monkeys also dem-
onstrated that females who were iron deficient during pregnancy
were more likely to give birth to babies prone to develop ID (al-
77
though, in that study, no baby was born with iron deficiency).
However, the association between maternal iron status (com-
monly determined by serum ferritin levels) and infant iron status is
unclear in human studies. In a convenience sample of 39 women with
uncomplicated pregnancies without anemia, ferritin levels dichoto-
mized by higher or lower than 10 ng/mL had no significant associ-
ation with cord blood hemoglobin (P = 1.000) or cord blood ferritin
(P = 0.375).14 In another study, maternal serum ferritin did not cor-
78
relate with cord blood ferritin (r = 0.168, P = 0.108) and maternal
serum ferritin less than 20 g/L or more than 20 g/L also did not result
in any difference in cord serum ferritin.79 When analyzing the pla-
cebo arm of an iron intervention study in a cohort of healthy mothers
who delivered term babies (and excluding mother–­baby dyads with
high cord ferritin as a marker of inflammation), those who had iron
deficiency at or near term had babies with lower levels of cord fer-
ritin compared with those born of mothers without iron deficiency
(96.3 mg/L, 95% CI, 91.3–­101.6 vs. 115.9 mg/L, 95% CI, 105.0–­
127.8).80 A large cohort with over 3000 mother–­baby dyads identi-
fied a small correlation (Pearson 0.07, P < 0.001) between maternal
and cord serum ferritin while identifying a cut-­off of 13.6 mg/L of ma-
ternal ferritin, which determined lower cord ferritin (179 ± 80 mg/L,
n = 1314 vs. 167 ± 75 mg/L, n = 1933; P < 0.001). Different thresholds
were used in another study that revealed this same pattern in babies
at term, where cord ferritin was higher in those born of mothers with
serum ferritin levels more than 10 μg/L (134.36 μg/L) versus mothers
81
with serum ferritin levels less than 10 μg/L (60.53 μg/L).
Other iron biomarkers have been used to correlate maternal and in-
fant iron levels. Cord soluble transferrin receptor (sTfR) was not found
to be significantly different between infants born to mothers with low
ferritin (<20 μg/L) or adequate ferritin (>60 μg/L) in early pregnancy,
nor with or without anemia (hemoglobin threshold 110 g/L) at more
than one prenatal visit.79 While animal data show lower iron levels in
pups born to iron-­deficient mothers in several compartments (fetal
serum, total iron, and fetal liver), the fundamental differences in the
biology of animals and humans (e.g. reliance on recycled/dietary iron,
placental structure, gestation duration, eating habits) make it impera-
tive that more data are derived from human studies.
6 | M ATE R N A L I RO N D E FI C I E N C Y A N D
I N FEC TI O N
Determining ID in the presence of infections that often cause in-
flammation is complex due to the effects of inflammation on iron
| 19
biomarkers. 20 Few studies have reported the impact of maternal
ID on either maternal or neonatal infection risk. The notable ex-
ceptions are studies conducted in areas of malaria transmission,
where the relationship between iron status and maternal infec-
tion, placental infection, and neonatal infection has been evalu-
ated. However, this relationship may be confounded not only by
the definition of ID itself but also by parasite species, exposure,
gravidity, diagnosis timing and tools, and uptake of preventative
treatment during pregnancy.
6.1 | Maternal infection
Studies in areas endemic to Plasmodium falciparum and P. vivax
generally describe an inverse relationship between maternal iron
surrogates and infection. A systematic review and analysis of the
relationship between maternal iron status and malaria infection
evaluating 12 studies (three case–­control and nine cross-­sectional)
up to 2014 revealed that women with ID defined by serum ferri-
tin levels adjusted for inflammation had a reduced risk of malaria
parasitemia during pregnancy82 (pooled odds ratio 0.35; 95% CI,
0.24–­0.51; I2 59.2%). It is worthwhile noting that ID, defined by any
other marker, was not associated with an increased risk of malaria
infection.82 A secondary analysis of a large randomized controlled
trial of malaria treatment during pregnancy, using serum ferritin
levels less than 15 mg/L to classify women as iron deficient before
week 27 of gestation (after adjustment for the markers of inflam-
mation CRP and alpha-­1-­acid glycoprotein (AGP), and parasitemia),
confirmed a reduced odds of concurrent malaria parasitemia in
iron-­deficient women (adjusted odds ratio 0.50; 95% CI, 0.38–­0.66,
P < 0.001). 27 This association was still true at delivery, with low fer-
ritin levels before week 27 showing an association with decreased
odds of peripheral infection (adjusted odds ratio 0.68; 95% CI, 0.46–­
1.00, P < 0.050). 27 Interestingly, these associations were only seen
in primigravidae (who, in areas of high transmission, and due to their
lack of previous exposure to parasite antigens that specifically bind
to the placenta, are more susceptible to infection83). 27
Outside of the malaria sphere, women early in pregnancy (mean
gestational age 9.2 ± 2.6 weeks) and with a healthy vaginal micro-
flora were found to have lower levels of sTfR (1.15 mg/L, n = 87)
compared with those with a disturbed microflora (1.37 mg/L, n = 18)
(P = 0.008).84 Interestingly, stratification by serum ferritin levels did
not show this association.84 Regarding SARS-­CoV-­2 infection and
COVID-­19, there remain limited data on associations between ma-
ternal iron status and risk of adverse outcomes.85 One retrospec-
tive study conducted in Romania found that within SARS-­CoV-­2
positive women (n = 95), the presence of IDA was associated with a
higher prevalence of small-­for-­gestational-­age babies (anemic 35%
vs. nonanemic 14.5%, P = 0.019). Additionally, iron markers (ferritin
levels, transferrin saturation, and circulating iron concentration) in
women with IDA (n = 143) were higher in those with SARS-­CoV-­2 in-
fection than in SARS-­CoV-­2 negative women86; however, it is impos-
sible to ascertain the directions or causality of these associations.
20 | ATAIDE et al.
6.2 | Placental infection
The presence of placental infections in the context of ID has re-
ceived little attention. Infection with Plasmodium falciparum during
pregnancy often results in the accumulation of parasites in the pla-
centa, particularly in the absence of previous exposure to the para-
sites during pregnancy.83,87 A systematic review of the association
between iron status and malaria infection during pregnancy could
not confirm a higher risk of placental infection in iron-­deficient ver-
sus iron-­replete women (two studies, pooled odds ratio 0.34; 95%
CI, 0.11–­1.10; I2 75.8%).82 However, this was certainly confounded
by the different definitions and methods of diagnosing placental in-
fection (placental malaria by histological evaluation—­either as a sim-
ple yes or no, or evaluating past, chronic, and active infections—­or
blood smear), as well as by the different definitions and timing of
measuring ID.82 This lack of consistency of approaches is again evi-
dent in two studies from Papua New Guinea, published after that
review. One study found no association between ID (n = 199/279
women, ferritin <15 μg/L at 30–­34 weeks of gestation) and placen-
tal P. falciparum (detected by placental blood smear or placental
histology), 26 while another study found a protective effect of iron
deficiency (n = 1226/1888 women, ferritin <15 μg/L—­adjusted for
inflammation—­before 27 weeks of gestation) and placental malaria
(only in the women with past malaria identified by histology, but not
in women with either active infection by histology, or with positive
placental blood). 27
6.3 | Neonatal infection
Apart from the risk of vertical transmission, maternal infections can
impair neonatal immune development, immune responses, and sus-
ceptibility to infection.88 However, little data exist on how low ma-
ternal iron stores may contribute to infection susceptibility in the
fetus and newborn.30
7 | CO N C LU S I O N S
Our understanding of the effect of iron deficiency during preg-
nancy on maternal health and the developing placenta and fetus
has advanced substantially. Animal models of iron deficiency have
contributed immensely to the understanding of these mechanisms
and will continue to play a critical role. However, ultimately, it
will be essential to adopt an experimental medicine approach to
human pregnancies with studies well designed and powered to
answer questions such as: (1) What is the effect of the timing and
duration of antenatal iron deficiency on placental and fetal de-
velopment? (2) What can placentas from women exposed to iron
deficiency tell us about how iron is used, regulated, and trafficked
in the placenta and how the fetus responds to this? (3) How does
the timing and duration of antenatal iron deficiency influence the
development of infant immunity, susceptibility to infection, and
response to vaccination? Addressing these questions will ulti-
mately yield enhanced evidence to combat iron deficiency in preg-
nant women worldwide.
AU T H O R C O N T R I B U T I O N S
Ricardo Ataide and Katherine Fielding performed the literature
search and selected the manuscripts for review. Ricardo Ataide
drafted the manuscript. Sant-­Rayn Pasricha and Cavan Bennett criti-
cally reviewed and edited the manuscript. All authors reviewed the
final version.
C O N FL I C T O F I N T E R E S T S TAT E M E N T
SRP and CB report support for the present work from the National
Health and Medical Research Council of Australia. Outside of the
published work, KF reports a PhD stipend from the Hematology
Society of Australia and New Zealand and technical consultant fees
from the WHO.
DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
REFERENCES
1. Stevens GA, Paciorek CJ, Flores-­Urrutia MC, et al. National, regional,
and global estimates of anaemia by severity in women and children
for 2000–­19: a pooled analysis of population-­representative data.
Lancet Glob Health. 2022;10:e627-­e639.
2. World Health Organization. Global Health Observatory. Prevalence
of anaemia in pregnant women aged 15–­49. Accessed January 12,
2023. https://www.who.int/data/gho/indic​ator-­metad​ata-­regis​
try/imr-­detai​ls/4552
3. Chaparro CM, Suchdev PS. Anemia epidemiology, pathophysiology,
and etiology in low-­and middle-­income countries. Ann N Y Acad Sci.
2019;1450:15.
4. World Health Organization. Nutritional Anaemias: Tools for Effective
Prevention. WHO; 2017.
5. Nestel P, INACG Steering Committee. Adjusting Hemoglobin Values
in Program Surveys. INACG; 2002. Accessed December 6, 2022.
https://pdf.usaid.gov/pdf_docs/PNACQ​927.pdf
6. Sangkhae V, Nemeth E. Placental iron transport: the mechanism
and regulatory circuits. Free Radic Biol Med. 2019;133:254-­261.
7. Daru J, Zamora J, Fernández-­Félix BM, et al. Risk of maternal
mortality in women with severe anaemia during pregnancy and
post partum: a multilevel analysis. Lancet Glob Health. 2018;6:​
e548-­e554.
8. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW.
Anaemia, prenatal iron use, and risk of adverse pregnancy out-
comes: systematic review and meta-­analysis. BMJ. 2013;346:f3443.
9. Nair M, Knight M, Kurinczuk J. Risk factors and newborn outcomes
associated with maternal deaths in the UK from 2009 to 2013: a
national case-­control study. BJOG. 2016;123:1654-­1662.
10. Harvey LJ, Armah CN, Dainty JR, et al. Impact of menstrual blood
loss and diet on iron deficiency among women in the UK. Br J Nutr.
2005;94:557-­564.
11. Venkata Surekha M, Singh S, Sarada K, et al. Study on the effect of
severity of maternal iron deficiency anemia on regulators of angio-
genesis in placenta. Fetal Pediatr Pathol. 2019;38:361-­375.
12. McArdle HJ, Gambling L, Kennedy C. Iron deficiency during preg-
nancy: the consequences for placental function and fetal outcome.
Proc Nutr Soc. 2014;73:9-­15.
ATAIDE et al.
13. Cao C, Prado MA, Sun L, et al. Maternal iron deficiency modulates
placental transcriptome and proteome in mid-­gestation of mouse
pregnancy. J Nutr. 2021;151:1073-­1083.
14. Sangkhae V, Fisher AL, Wong S, et al. Effects of maternal iron
status on placental and fetal iron homeostasis. J Clin Invest.
2020;130:625-­6 40.
15. Cao C, Fleming MD. The placenta: the forgotten essential organ of
iron transport. Nutr Rev. 2016;74:421-­431.
16. Bradley J, Leibold EA, Harris ZL, et al. Influence of gestational age
and fetal iron status on IRP activity and iron transporter protein ex-
pression in third-­trimester human placenta. Am J Physiol Regul Integr
Comp Physiol. 2004;287:R894-­R901.
17. McDonald EA, Gundogan F, Olveda RM, Bartnikas TB, Kurtis JD,
Friedman JF. Iron transport across the human placenta is regulated
by hepcidin. Pediatr Res. 2022;92:396-­3 40.
18. Mcardle HJ, Lang C, Hayes H, Gambling L. Role of the placenta in
regulation of fetal iron status. Nutr Rev. 2011;69:17-­22.
19. Bastin J, Drakesmith H, Rees M, Sargent I, Townsend A. Localisation
of proteins of iron metabolism in the human placenta and liver. Br J
Haematol. 2006;134:532-­543.
20. Ganz T, Nemeth E. Iron homeostasis in host defence and inflamma-
tion. Nat Rev Immunol. 2015;15:500-­510.
21. Soares MP, Weiss G. The iron age of host-­microbe interactions.
EMBO Rep. 2015;16:1482-­1500.
22. Okala SG, Darboe MK, Sosseh F, et al. Impact of nutritional supple-
mentation during pregnancy on antibody responses to diphtheria-­
tetanus-­pertussis vaccination in infants: a randomised trial in The
Gambia. PLoS Med. 2019;16:1-­20.
23. Stoffel NU, Uyoga MA, Mutuku FM, et al. Iron deficiency anemia at
time of vaccination predicts decreased vaccine response and iron
supplementation at time of vaccination increases humoral vaccine
response: a birth cohort study and a randomized trial follow-­up
study in Kenyan infants. Front Immunol. 2020;11:1313.
24. Georgieff MK. The importance of iron deficiency in pregnancy on
fetal, neonatal, and infant neurodevelopmental outcomes. Int J
Gynecol Obstet. 2023;162(Suppl. 2):83-­88.
25. Senga EL, Harper G, Koshy G, Kazembe PN, Brabin BJ. Reduced risk
for placental malaria in iron deficient women. Malar J. 2011;10:47.
26. Fowkes FJI, Moore KA, Opi DH, et al. Iron deficiency during preg-
nancy is associated with a reduced risk of adverse birth outcomes
in a malaria-­endemic area in a longitudinal cohort study. BMC Med.
2018;16:1-­10.
27. Unger HW, Bleicher A, Kaius MO, Aitken EH, Rogerson SJ.
Associations of maternal iron deficiency with malaria infection in a co-
hort of pregnant Papua new Guinean women. Malar J. 2022;21:153.
28. Kabyemela ER, Fried M, Kurtis JD, Mutabingwa TK, Duffy
PE. Decreased susceptibility to plasmodium falciparum in-
fection in pregnant women with iron deficiency. J Infect Dis.
2008;198(198):163-­166.
29. Brabin L, Brabin BJ, Gies S. Maternal iron –­infection interactions
and neonatal mortality, with an emphasis on developing countries.
Nutr Rev. 2013;71:528-­540.
30. Brabin L, Brabin BJ, Gies S. Influence of iron status on risk of mater-
nal or neonatal infection and on neonatal mortality with an empha-
sis on developing countries. Nutr Rev. 2013;71:528-­540.
31. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93:1721-­1741.
32. Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders
revisited in the hepcidin era. Haematologica. 2020;105:260-­272.
33. Moreira AC, Mesquita G, Gomes MS. Ferritin: an inflammatory
player keeping iron at the core of pathogen-­ host interactions.
Microorganisms. 2020;8:589.
34. Shawki A, Anthony SR, Nose Y, et al. Intestinal DMT1 is critical for
iron absorption in the mouse but is not required for the absorp-
tion of copper or manganese. Am J Physiol Gastrointest Liver Physiol.
2015;309:G635-­G647.
| 21
35. Aschemeyer S, Qiao B, Stefanova D, et al. Structure-­function anal-
ysis of ferroportin defines the binding site and an alternative mech-
anism of action of hepcidin. Blood. 2018;131:899-­910.
36. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular
iron efflux by binding to ferroportin and inducing its internalization.
Science. 2004;306:2090-­2093.
37. Billesbølle CB, Azumaya CM, Kretsch RC, et al. Structure of
hepcidin-­bound ferroportin reveals iron homeostatic mechanisms.
Nature. 2020;586:807-­811.
38. Ganz T. Hepcidin and iron regulation, 10 years later. Blood.
2011;117:4425-­4 433.
39. Koenig MD, Tussing-­ Humphreys L, Day J, Cadwell B, Nemeth
E. Hepcidin and iron homeostasis during pregnancy. Nutrients.
2014;6:3062-­3 083.
40. O'Brien KO. Maternal, fetal and placental regulation of placental
iron trafficking. Placenta. 2022;125:47-­53.
41. van Santen S, Kroot JJC, Zijderveld G, Wiegerinck ET, Spaanderman
MEA, Swinkels DW. The iron regulatory hormone hepcidin is de-
creased in pregnancy: a prospective longitudinal study. Clin Chem
Lab Med. 2013;51:1395-­1401.
42. Bah A, Pasricha S-­R , Jallow MW, et al. Serum hepcidin concentra-
tions decline during pregnancy and may identify iron deficiency:
analysis of a longitudinal pregnancy cohort in The Gambia. J Nutr.
2017;147:1131-­1137.
43. Roberts H, Bourque SL, Renaud SJ. Maternal iron homeosta-
sis: effect on placental development and function. Reproduction.
2020;160:R65-­R78.
44. Fisher AL, Nemeth E. Iron homeostasis during pregnancy. Am J Clin
Nutr. 2017;106:1567S-­1574S.
45. Maltepe E, Bakardjiev AI, Fisher SJ. The placenta: transcriptional,
epigenetic, and physiological integration during development. J Clin
Invest. 2010;120:1016-­1025.
46. Maltepe E, Fisher SJ. Placenta: the forgotten organ. Annu Rev Cell
Dev Biol. 2015;31:523-­552.
47. Toblli JE, Cao G, Oliveri L, Angerosa M. Effects of iron deficiency
anemia and its treatment with iron polymaltose complex in preg-
nant rats, their fetuses and placentas: oxidative stress markers and
pregnancy outcome. Placenta. 2012;33:81-­87.
48. Wong C-­ T, Sana N. Inter-­ relationships of storage iron in the
mother, the placenta and the newborn. Acta Obstet Gynecol Scand.
1990;69:613-­616.
49. Kwan STC, Kezer CA, Helfrich KK, et al. Maternal iron nutriture
modulates placental development in a rat model of fetal alcohol
spectrum disorder. Alcohol. 2020;84:57-­66.
50. Roberts H, Woodman AG, Baines KJ, Jeyarajah MJ, Bourque SL,
Renaud SJ. Maternal iron deficiency alters trophoblast differenti-
ation and placental development in rat pregnancy. Endocrinology.
2021;162:bqab215.
51. Recalcati S, Minotti G, Cairo G. Iron regulatory proteins: from mo-
lecular mechanisms to drug development. Antioxid Redox Signal.
2010;13:1593-­1616.
52. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two
to tango: regulation of mammalian iron metabolism. Cell.
2010;142:24-­38.
53. McCormick MC. The contribution of low birth weight to infant mor-
tality and childhood morbidity. N Engl J Med. 1985;312:82-­90.
54. Al-­Hashimi LM, Gambling L, McArdle HJ. The effect of iron defi-
ciency on osmotic sensitivity of red blood cells from neonatal rats
and their mothers. J Membr Biol. 2015;248:1199-­1206.
55. Hubbard AC, Bandyopadhyay S, Wojczyk BS, Spitalnik SL, Hod EA,
Prestia KA. Effect of dietary iron on fetal growth in pregnant mice.
Comp Med. 2013;63:127-­135.
56. Hubbard AC, Bandyopadhyay S, Wojczyk BS, Spitalnik SL, Hod EA,
Prestia KA. Effect of iron deficiency on fetal growth in the pregnant
mouse. J Am Assoc Lab Anim Sci. 2012;51:687.
22 | ATAIDE et al.
57. Mwangi MN, Roth JM, Smit MR, et al. Effect of daily antenatal iron
supplementation on plasmodium infection in kenyan women: a ran-
domized clinical trial. JAMA. 2015;314:1009-­1020.
58. Ali El-­Farrash R, Rahman Ismail EA, Shafik NA. Cord blood iron
profile and breast milk micronutrients in maternal iron deficiency
anemia. Pediatr Blood Cancer. 2012;58:233-­238.
59. Vazirinejad R, Esmaeili A, Vazirinejad H, Hassanshahi G. Ferritin
concentration and pregnancy outcome: linear models for predicting
birthweight and birth length. Food Nutr Bull. 2007;28:419-­425.
60. Ribot B, Aranda N, Viteri F, Hernández-­Martínez C, Canals J, Arija
V. Depleted iron stores without anaemia early in pregnancy carries
increased risk of lower birthweight even when supplemented daily
with moderate iron. Hum Reprod. 2012;27:1260-­1266.
61. Aranda N, Ribot B, Garcia E, Viteri FE, Arija V. Pre-­pregnancy iron
reserves, iron supplementation during pregnancy, and birth weight.
Early Hum Dev. 2011;87:791-­797.
62. Puerto A, Trojan A, Alvis-­Zakzuk NR, et al. Iron status in late preg-
nancy is inversely associated with birth weight in Colombia. Public
Health Nutr. 2021;24:5090-­5100.
63. Hanieh S, Ha TT, de Livera AM, et al. Antenatal and early infant pre-
dictors of postnatal growth in rural Vietnam: a prospective cohort
study. Arch Dis Child. 2015;100:165-­173.
64. Rahman SM, Siraj MS, Islam MR, Rahman A, Ekström EC. Association
between maternal plasma ferritin level and infants' size at birth: a
prospective cohort study in rural Bangladesh. Glob Health Action.
2021;14:1870421.
65. Pasricha SR, Mwangi MN, Moya E, et al. Ferric carboxymaltose ver-
sus standard-of-care oral iron to treat second-trimester anaemia in
Malawian pregnant women: a randomised controlled trial. Lancet.
2023;401:1595-­1609.
66. Ervasti M, Sankilampi U, Heinonen S, Punnonen K. Early signs of
maternal iron deficiency do not influence the iron status of the
newborn, but are associated with higher infant birthweight. Acta
Obstet Gynecol Scand. 2009;88:83-­90.
67. Pasricha S-­ R , Hasan MI, Braat S, et al. Benefits and risks of
iron interventions in infants in rural Bangladesh. N Engl J Med.
2021;385:982-­995.
68. Ni S, Yuan Y, Kuang Y, Li X. Iron metabolism and immune regulation.
Front Immunol. 2022;13:816282.
69. Nairz M, Weiss G. Iron in infection and immunity. Mol Asp Med.
2020;75:100864.
70. Cronin SJF, Woolf CJ, Weiss G, Penninger JM. The role of iron regu-
lation in immunometabolism and immune-­related disease. Front Mol
Biosci. 2019;6:116.
71. Frost JN, Tan TK, Abbas M, et al. Hepcidin-­mediated hypoferremia
disrupts immune responses to vaccination and infection. Med (N Y).
2021;2:164-­179.e12.
72. Hassan TH, Badr MA, Karam NA, et al. Impact of iron deficiency
anemia on the function of the immune system in children. Medicine
(Baltimore). 2016;95:e5395.
73. Hur YG, Gorak-­Stolinska P, Lalor MK, et al. Factors affecting immu-
nogenicity of BCG in infants, a study in Malawi, The Gambia and the
UK. BMC Infect Dis. 2014;14:184.
74. Xiao M, Qiu Q, Pang X, et al. Immune response in infants after uni-
versal high-­dose hepatitis B vaccination: a community-­based study
in Beijing, China. Vaccine. 2015;33:5878-­5883.
75. Ahmad SM, Hossain MB, Monirujjaman M, et al. Maternal zinc sup-
plementation improves hepatitis B antibody responses in infants
but decreases plasma zinc level. Eur J Nutr. 2016;55:1823-­1829.
76. Osendarp SJM, Fuchs GJ, van Raaij JMA, et al. The effect of zinc
supplementation during pregnancy on immune response to hib and
BCG vaccines in Bangladesh. J Trop Pediatr. 2006;52:316-­323.
77. Lubach GR, Coe CL. Preconception maternal iron status is a risk
factor for iron deficiency in infant rhesus monkeys (Macaca mu-
latta). J Nutr. 2006;136:2345-­2349.
78. Chan KC, Tsun JGS, Li AM, Tam WH. Iron status of full-­term infants
in early infancy is not associated with maternal ferritin levels nor
infant feeding practice. Br J Nutr. 2022;127:1198-­1203.
79. Hay G, Refsum H, Whitelaw A, Melbye EL, Haug E, Borch-­Iohnsen
B. Predictors of serum ferritin and serum soluble transferrin recep-
tor in newborns and their associations with iron status during the
first 2 y of life 1-­3. Am J Clin Nutr. 2007;86:64-­73.
80. Hua Y, Kaciroti N, Jiang Y, et al. Inadequate iron stores in early term
neonates. J Perinatol. 2018;38:1017-­1021.
81. Kohli UA, Rajput M, Venkatesan S. Association of maternal hemo-
globin and iron stores with neonatal hemoglobin and iron stores.
Med J Armed Forces India. 2021;77:158-­164.
82. Sangaré L, van Eijk AM, ter Kuile FO, Walson J, Stergachis A. The
association between malaria and iron status or supplementation
in pregnancy: a systematic review and meta-­analysis. PLoS One.
2014;9:e87743.
83. Ataíde R, Mayor A, Rogerson SJ. Malaria, primigravidae, and anti-
bodies: knowledge gained and future perspectives. Trends Parasitol.
2014;30:85-­94.
84. Verstraelen H, Delanghe J, Roelens K, Blot S, Claeys G, Temmerman
M. Subclinical iron deficiency is a strong predictor of bacterial vag-
inosis in early pregnancy. BMC Infect Dis. 2005;5:55.
85. Ciapponi A, Bardach A, Comandé D, et al. COVID-­19 and preg-
nancy: an umbrella review of clinical presentation, vertical
transmission, and maternal and perinatal outcomes. PLoS One.
2021;16:e0253974.
86. Uta M, Neamtu R, Bernad E, et al. The influence of nutritional sup-
plementation for iron deficiency anemia on pregnancies associated
with SARS-­CoV-­2 infection. Nutrients. 2022;14:836.
87. Rogerson SJ, Desai M, Mayor A, Sicuri E, Taylor SM, van Eijk AM.
Burden, pathology, and costs of malaria in pregnancy: new develop-
ments for an old problem. Lancet Infect Dis. 2018;18:e107-­e118.
88. Dauby N, Goetghebuer T, Kollmann TR, Levy J, Marchant A.
Uninfected but not unaffected: chronic maternal infections during
pregnancy, fetal immunity, and susceptibility to postnatal infec-
tions. Lancet Infect Dis. 2012;12:330-­3 40.
How to cite this article: Ataide R, Fielding K, Pasricha S-R,
Bennett C. Iron deficiency, pregnancy, and neonatal
development. Int J Gynecol Obstet. 2023;162(Suppl. 2):14-22.
doi:10.1002/ijgo.14944