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Special Article

Influence of iron status on risk of maternal or neonatal

infection and on neonatal mortality with an emphasis on
developing countries
Loretta Brabin, Bernard J Brabin, and Sabine Gies

Infection is a major cause of neonatal death in developing countries. This review

investigates whether host iron status affects the risk of maternal and/or neonatal
infection, potentially contributing to neonatal death, and summarizes the iron
acquisition mechanisms described for pathogens causing stillbirth, preterm
birth, and congenital infection. In vitro evidence shows that iron availability
influences the severity and chronicity of infections that cause these negative
outcomes of pregnancy. In vivo evidence is lacking, as relevant studies of maternal
iron supplementation have not assessed the effect of iron status on the risk of
maternal and/or neonatal infection. Reducing iron-deficiency anemia among
women is beneficial and should improve the iron stores of babies; moreover, there is
evidence that iron status in young children predicts the risk of malaria and, possibly,
the risk of invasive bacterial diseases. Caution with maternal iron supplementation is
indicated in iron-replete women who may be at high risk of exposure to infection,
although distinguishing between iron-replete and iron-deficient women is currently
difficult in developing countries, where a point-of-care test is needed. Further
research is indicated to investigate the risk of infection relative to iron status in
mothers and babies in order to avoid iron intervention strategies that may result in
detrimental birth outcomes in some groups of women.
© 2013 International Life Sciences Institute

INTRODUCTION Nutritional recommendations include intermittent iron

In low-resource settings, up to 40% of all deaths in chil-
dren below the age of 5 years occur in the neonatal
period.1 Many neonatal deaths are due to perinatal infec-
tions,2 especially in preterm and growth-restricted babies
whose immunological responses may be impaired due to
underdevelopment of the complement system,3 impaired
immune functional reserve,4,5 and thymic involution.6
Improved prenatal and delivery care, as well as imple-
mentation of hygienic umbilical cord management,
should reduce exposure of newborns to infections.7
supplementation for women of reproductive age before
pregnancy8,9 and daily iron supplementation during
pregnancy.10 These interventions, which are aimed at
maintaining and improving maternal health and iron
nutrition, can reduce anemia during pregnancy and
change the iron endowment of the fetus and neonate.11
The benefits of improved maternal iron status might
be offset by an increased risk of maternal and/or neonatal
infection, due to the increased availability of iron to host
pathogens that cause perinatal infections. Detrimental
infection-related outcomes of iron supplementation in

Affiliations: L Brabin is with the Academic Unit of Obstetrics & Gynaecology, University of Manchester, Manchester, UK. BJ Brabin is with
the Child and Reproductive Health Group, Liverpool School of Tropical Medicine, Liverpool, UK, and the Global Child Health Group,
Emmakinderziekenhuis, Academic Medical Centre, Amsterdam, The Netherlands. S Gies is with the Department of Biomedical Sciences,
Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium.
Correspondence: L Brabin, Academic Unit of Obstetrics & Gynaecology, St. Mary’s Hospital, Oxford Road, Manchester M13 9WL, UK. E-mail:
loretta.brabin@manchester.ac.uk. Phone: +44-161-276-6388.
Key words: birth outcomes, infection, iron, maternal, neonatal, pregnancy, supplementation

doi:10.1111/nure.12049
528 Nutrition Reviews® Vol. 71(8):528–540
Figure 1 Routes by which iron-dependent pathogens cause uterine infection and neonatal morbidity and mortality.
References indicate iron-dependent mechanisms influencing each bacterial species.
pregnancy could affect large populations of women and
babies. For this reason, this review summarizes for the
first time the iron-acquisition strategies of pathogens
responsible for infection-related adverse pregnancy
outcomes. Focusing on microbial mechanisms of iron
acquisition is fundamental for addressing the nutritional
immunity hypothesis, which proposes that iron-deficient
subjects are relatively protected from infection by patho-
gens with iron-regulated virulence determinants, whereas
iron-replete subjects may be at increased risk of infection
when iron is provided.12
This review begins by describing the contribution
of infection to stillbirth, preterm birth (PTB), and con-
genital infections. Next, epidemiological evidence of the
effects of prenatal iron supplementation on neonatal
mortality is reviewed, as a high proportion of neonatal
deaths are infection related. The third section considers
whether detrimental pregnancy outcomes in women
with higher hemoglobin concentrations may lead to
altered risk of neonatal infection as a consequence of
enhanced maternal iron status. In the fourth section, an
overview is provided of the general mechanisms for iron
withholding in the host that are relevant to the risk of
maternal infection. Evidence from in vitro studies is
reviewed, showing that most of the common pathogens
that cause adverse birth outcomes utilize multiple iron-
acquisition mechanisms to counter host iron withhold-
ing. In the fifth section, the effects of neonatal iron
status are considered in relation to the risk of neonatal
infection and mortality. Finally, the implications for
future research are discussed.
Nutrition Reviews® Vol. 71(8):528–540
CONTRIBUTION OF INFECTION TO ADVERSE
BIRTH OUTCOMES
In developing countries, where stillbirth rates are
approximately 45 per 1,000 births,13 infections may
account for 50% of all stillbirths.14,15 In developed coun-
tries, inflammation and infection are suspected to be
involved in approximately 50% of PTB of unknown
cause.16 In newborns in the developing world, the greatest
single cause of perinatal death is PTB.14 Pregnancy out-
comes are determined by the virulence of the infective
organism, the gestational timing of infection, and the
availability of treatment. Fetal infection results either
from hematogenous infections acquired transplacentally
or from ascending genital tract infections that cause
chorioamnionitis and amniotic fluid infection. Neonatal
infections may also be acquired during delivery. The
routes of neonatal infection are summarized in
Figure 1.17–31
The iron-acquisition strategies of pathogens respon-
sible for such adverse birth outcomes are summarized
later in this review in the section on mechanisms regulat-
ing access of pathogens to iron. No direct relationship
between maternal iron status and the following birth out-
comes is yet established, although study of this topic is
limited.
Stillbirth
A fetal death, meaning death before delivery, can occur at
any stage of pregnancy. A fetal response, including
529
changes in fetal hepatic iron storage that were correlated
with infection severity, was observed to culminate in
second trimester abortion.32 A stillbirth is defined as no
sign of life in a neonate at delivery. Amniotic fluid infec-
tion often leads to death before 28 weeks of gestation.15
Common pathogenic causes of infections include
Ureaplasma urealyticum, Mycoplasma hominis, Klebsiella
spp., and members of the family Bacteroidaceae.33 Viru-
lent organisms, including Escherichia coli, enterococci,
and group B Streptococcus, are frequently found at
autopsy.34,35 Malaria is a leading cause of stillbirth in sub-
Saharan Africa. One meta-analysis reported an odds ratio
of 2.19 (95%CI 1.49–3.22, P<0.001) for malaria causing
stillbirth.36
Preterm birth
PTB, particularly spontaneous birth at less than 30 weeks
of gestation, is associated with the ascent of microorgan-
isms from the cervical/vaginal area, causing chorioam-
nionitis.37 Bacterial vaginosis (BV) is consistently
associated with at least a twofold increased risk of PTB.38
In BV, there is a massive overgrowth of vaginal organisms
such as Gardnerella vaginalis, Bacteroides spp., U. ure-
alyticum, and M. hominis.39 The pathogenesis of BV and
the mechanisms by which it may lead to PTB are poorly
understood, but the relationship is strongest in the first
trimester or early in the second trimester. Women with
BV early in pregnancy are likely to have persistent infec-
tion late in pregnancy.40 Some associated microbes such
as M. hominis and Gardnerella spp. tend to be of low
virulence and can cause subclinical infection that leads to
premature rupture of membranes.37 Aerobic vaginitis
is a specific condition in which vaginal lactobacilli are
replaced by intestinal bacteria such as E. coli.41 Other
maternal bacterial infections that predispose to PTB
include asymptomatic bacteriuria,42 pyelonephritis,43
pneumonia,44 and tuberculosis.45 Plasmodium falciparum
malaria is a common parasitic infection that causes PTB
and low birth weight in sub-Saharan Africa.46
Congenital infections
Congenital infections, acquired at delivery, are common
causes of adverse birth outcomes. For example, chlamy-
dial infections acquired via an infected cervix affect 50%–
75% of babies of infected mothers, leading to neonatal
conjunctivitis (20%–50%) and neonatal pneumonia fol-
lowing nasopharyngeal infection.47 Over half of mothers
with vaginal Group B Streptococcus colonization will
transmit the infection during labor, resulting in the risk of
neonatal sepsis.48 Yeast infections, notably by Candida al-
bicans, are also acquired through vertical transmis-
sion, and disseminated neonatal fungal disease is well
530
described.26 Some countries screen mothers for early
diagnosis of toxoplasmosis49 or the presence of Group B
Streptococcus,50 with diagnosis based on a combination of
clinical features and/or a range of laboratory tests. Screen-
ing for chlamydia infection and gonorrhea may also be
recommended, but achieving compliance with program
guidelines can be challenging.51 The resources needed for
routine prenatal screening are not available in most
developing countries.
EPIDEMIOLOGICAL STUDIES OF THE EFFECT OF
PRENATAL IRON SUPPLEMENTATION ON
NEONATAL MORTALITY
A large number of intervention studies to alleviate iron
deficiency and iron deficiency anemia in pregnancy have
been performed,52 including several large observational
studies, although few randomized trials have been
conducted.53–61 The epidemiological evidence to support
daily iron supplementation in pregnancy was provided by
a Cochrane Review that included 49 trials.10 It concluded
that daily supplementation reduced maternal anemia, but
it identified almost no data related to PTB, low birth
weight, maternal or neonatal infection, or child survival.
Table 1 summarizes the estimates of risk of neonatal mor-
tality in iron- and folic-acid-supplemented groups com-
pared with controls in randomized trials. Neonatal
mortality was significantly decreased in the Chinese trial
in the intervention arm57 and was nonsignificantly
reduced in the other studies. The exception was the
Finnish study, in which mortality risk was increased.55 A
Cochrane review that included three of these studies
(from Nepal, Finland, and Iran) reported a relative risk
(RR) for neonatal mortality of 0.93 (95%CI 0.67–1.29).10
These trials provide some evidence of decreased
perinatal and neonatal mortality with iron supplementa-
tion in nonmalarious areas, although the effect is modest.
In a study utilizing routinely collected data from the
Indonesian Demographic and Health Survey, a signifi-
cantly lower under-5 mortality was reported when iron
supplements and folic acid were taken, notably from the
first trimester onward (adjusted hazard ratio 0.62,
95%CI 0.49–0.78; P < 0.001).62 The same study reported a
lower risk of neonatal mortality in supplemented com-
pared with nonsupplemented women (adjusted hazard
ratio 0.69, 95%CI 0.49–0.97; P = 0.035). A difficulty with
these cross-sectional data is that nearly all women pre-
sented for prenatal care, and the analysis did not control
for the number of prenatal visits. Thus, the benefits of
prenatal care (which might include treatment of infec-
tion) could account for the reductions in mortality
observed. The findings in this Indonesian study also may
be influenced by folic acid supplementation, as folate
Nutrition Reviews® Vol. 71(8):528–540
 supplementation alone has been reported to reduce neo-

Hemminki & Rimpelä (1991)55

Table 1 Estimates of risk of neonatal or perinatal mortality in randomized controlled trials of iron and folic acid supplementation in pregnancy compared with
natal deaths.54
A meta-analysis of 12 randomized controlled trials

Christian et al. (2003)54

Christian et al. (2003)54
in pregnant women, which compared multiple micronu-

Preziosi et al. (1997)60

Zeng et al. (2008)57
Zeng et al. (2008)57
Ziaei et al. (2007)56
trient supplementation with iron and folic acid supple-
mentation (containing 30 mg or 60 mg of elemental
iron), concluded that multiple micronutrients during
Reference

pregnancy did not result in any reduction in stillbirths or

in early or late neonatal deaths compared with iron-folic
acid alone.63 None assessed the risk of neonatal bacterial
infection or malaria, even though four trials were in
malarious regions. The exception in this meta-analysis
perinatal mortality

was a study in Indonesia, which reported that combined

0.80 (0.55 –1.17)d
1.32 (0.58–3.00)d
d

0.84 (0.59–1.19)d
0.14 (0.02–1.13)d
0.80 (0.50–1.27)c

c
0.48 (0.12–1.91)
0.53 (0.29–0.97)

fetal loss and neonatal deaths were reduced by 11% (RR

Neonatal or

0.89, 95%CI 0.81–1.00, P = 0.045), with similar effects

RR (95%CI)

observed in undernourished (RR 0.85, 95%CI 0.73–0.98,

P = 0.022) or anemic women (RR 0.71, 95%CI 0.58–0.87,
P = 0.001).64 As all trial participants received iron supple-
mentation, an association between iron supplementation
and neonatal mortality could not be determined.
intervention

Safety concerns of daily iron supplementation

during pregnancy were readdressed in a recent Cochrane
Size of

group

Hemoglobin changes reported: Nepal, +14 g/L61; China, +5 g/L57; Niger, 23.8% decreased prevalence of anemia.60
772
801
1,336
370
1546
1546
99

Review,65 which reported the benefits and harms of inter-

mittent versus daily iron supplementation in relation to
neonatal and pregnancy outcomes. A stated limitation of
the review was the low or very low quality of the 18 trials
compliance

included. None reported on maternal iron deficiency at

Percent

77–80
77–80

term, infections during pregnancy, anemia during the

91.9
>95

NA

first 6 months after birth, or neonatal infections or deaths.

80

Women receiving daily supplements had an increased

risk of developing high (>13 g/dL) hemoglobin levels in
Iron/folate dose

mid- and late pregnancy (average RR 2.08, 95%CI 1.49–

60 mg/400 mg
60 mg/400 mg

60 mg/400 mg

2.70, 13 studies). The review provided cautious support

50 mg/1 mg

for recommending intermittent rather than daily iron

100 mgb

100 mgb

supplementation among those pregnant women who are

not anemic and have adequate prenatal care.
Five studies have reported the effects of prenatal iron
Abbreviations: FA, folic acid; RR, relative risk, NA, not available.
control groups receiving no iron supplementation.

treatments on the prevalence of malaria in semi-immune

Placebo and FA

women.66–70 Three used oral supplements,66–68 and in

Type of control

two, parenteral iron was administered to iron-deficient

Vitamin A

anemic women.69,70 One showed that recent hematinic

Placebo
No iron

use increased the risk of Plasmodium vivax infection,68

FA

and the two randomized placebo-controlled trials of

oral iron supplementation reported benefits without
Iron intervention without folic acid.

increased risk of malaria66,67 except in multigravidae with

Study year(s)

sickle cell trait.67 The two retrospective analyses, which

1998–2001

1985–1986
2005–2006
2002–2006

reported increased prevalence of P. falciparum at delivery

with use of prenatal parenteral iron, were confounded.65,66
1996

Neonatal mortality.
Perinatal mortality.

This is because recruited women had severe anemia

earlier in pregnancy and, as a result, would have been
more likely to have had malarial anemia, regardless of
Country

Finland

receiving parenteral iron.

Nepala

Nigera
China
Iran

In summary, few iron supplementation studies

b

during pregnancy have assessed infection risk, other than

a

Nutrition Reviews® Vol. 71(8):528–540 531

for malaria, for which no clear conclusions can yet be
drawn. Other important infective causes of PTB, still-
birth, or congenital infections have not been addressed.
Although some gains in terms of reduced neonatal mor-
tality have been demonstrated with daily iron and folic
acid supplementation during pregnancy, the mechanisms
involved have not been identified. This is important
because the effects may be heterogenous with some, but
not all, women who derive benefits.
POTENTIAL BENEFICIAL AND DETRIMENTAL EFFECTS
OF PRENATAL IRON SUPPLEMENTATION ON
INFECTION-RELATED PREGNANCY OUTCOMES
Figure 2 shows a schematic representation of the relation-
ship between maternal hemoglobin concentration and
poor pregnancy outcomes for women from industrialized
countries. This figure is derived from several studies71–78
that have variously reported pregnancy outcomes (low
birth weight, stillbirth, PTB, and perinatal, neonatal, and
maternal mortality) in relation to hemoglobin concentra-
tion in early and/or late gestation. Optimal pregnancy
Figure 2 U-shaped association of maternal hemoglobin
concentration with risk of adverse pregnancy
outcomes.
The figure shows the relationship between hemoglobin
concentration and risk of dysfunctional responses in terms
of adverse pregnancy outcomes that include low birth
weight, preterm birth, and perinatal mortality. Cutoff values
are as follows: anemia, <11 g/dL; low hemoglobin, <9.0 g/
dL; and high hemoglobin, >13 g/dL.
532
outcomes were observed mostly at maternal hemoglobin
concentrations slightly below 11 g/dL (either early or late
in pregnancy), which is the international cutoff value for
defining anemia during pregnancy, although the evidence
suggests that lower values may be preferable. Healthy
Spanish women, for example, who maintained hemoglo-
bin levels between 9.5 and 12.5 g/dL had infants with
optimal birth weights.79 Populations with mean maternal
hemoglobin levels below the lower limit of 9.5 g/dL,
however, are located mainly in areas where chronic
enteric blood loss, malaria, other hemolytic conditions, or
maternal malnutrition are common.
The U-shaped association between adverse preg-
nancy outcomes and higher hemoglobin values (Figure 2)
in industrialized countries has been attributed mainly to
blood volume dynamics, which are more important in
mid- and late pregnancy.80 Increased oxidative stress has
also been implicated.77 In a study of nonanemic Mexican
women who received daily versus weekly iron supple-
mentation, subjects with hemoconcentration at gesta-
tional week 28 had a significantly higher RR of low-birth-
weight infants (RR 6.2, 95%CI 1.5–26.6) and premature
delivery (RR 7.8, 95%CI 1.4–24.7).77 In a later report from
the same population, daily – but not weekly – iron supple-
mentation during pregnancy was associated with oxida-
tive stress in nonanemic women.81 A possible limitation
to this later study was that C-reactive protein or other
indicators of inflammation were not measured.
Mechanisms related to iron status and risk of infec-
tion should also be considered in relation to pregnancy
outcomes for women with either high or low hemoglobin.
For example, impaired immune responsiveness due to
iron deficiency might influence the risk of infection in
anemic women.12 One US study reported that pregnant
women who were iron deficient or anemic at study entry
(approximately 15 weeks of gestation) were more likely to
have ferritin levels that did not decline by 28 weeks of
gestation.82 These women had a twofold increased risk of
chorioamnionitis and a sixfold increased risk of influenza
at term. The authors attributed nondeclining ferritin con-
centrations to increased susceptibility to infection due to
iron deficiency at study entry. Host susceptibility was also
inferred in a study reporting mildly disturbed vaginal
flora in the first trimester in 10 iron-deficient Belgian
women, but not in healthy controls.83
Conversely, in iron-replete nonanemic subjects,
increased susceptibility to iron-requiring enteric patho-
gens or increased severity of infection could occur,
particularly if these women received additional iron
supplementation. For example, an in vitro study reported
that greater availability of free iron increased the patho-
genic potential of Salmonella typhimurium and other
enteric pathogens at the intestinal epithelial interface.84
Perineal contamination could increase the risk of
Nutrition Reviews® Vol. 71(8):528–540
chorioamnionitis as well as the risk of neonatal infection.
The pathogenic potential of Salmonella spp. as a cause of
neonatal sepsis in African countries is well described.35
MECHANISMS REGULATING ACCESS OF
PATHOGENS TO IRON
Systemic host iron regulation
The host restricts free iron from becoming available to
pathogens by several mechanisms, shown below.
Decreased release of tissue iron into the circulation. This
results from increased hepatic synthesis of hepcidin.85
Hepcidin binds the iron exporter ferroportin, normally
present on macrophages, enterocytes, and placenta, and
induces its internalization and degradation. This results
in cellular iron retention through reduced iron absorp-
tion and inhibited iron recycling.86,87 Placental uptake of
dietary heme and nonheme iron has also been related to
maternal hepcidin and maternal/neonatal iron status.88
Low maternal hepcidin levels in late pregnancy were
reported in a nonanemic population.89 Although this
would be expected to allow placental iron to accumulate
at a gestational age when fetal iron acquisition is at its
highest, it was not correlated with cord blood hepcidin.89
Hepcidin synthesis is regulated by erythropoietic
activity, changes in body iron stores, and inflammation or
infection. Genetic disorders can either increase90 or
decrease87 hepcidin synthesis. In hereditary hemochro-
motosis, mutations in the HFE gene are associated with
iron overload. Their influence on the risk of infection is
uncertain, although their absence in a murine model
enhanced host resistance to systemic Salmonella infection
by inducing expression of the iron-capturing peptide
lipocalin 2.91 Ferroportin mRNA also has an iron-
responsive element and, under low-iron conditions, its
protein levels are reduced.92 More data are needed on the
determinants of systemic hepcidin concentrations during
pregnancy and the impact of hepcidin on placental func-
tion. Variations with gestational age or in relation to man-
agement of parturition are largely unexplained.93
Downregulation of transferrin (TF) receptors on the
cell surface by inflammatory cytokines. This decreases
iron availability to intracellular microorganisms
such as Legionella pneumophila and Mycobacterium
tuberculosis.94,95
Restriction of iron supply to extracellular pathogens by the
iron-binding glycoproteins TF and lactoferrin (LF).96
These two proteins have similar iron-binding functions,
and their high iron affinity limits the amount of free iron
available for infectious organisms. TF is far more abun-
Nutrition Reviews® Vol. 71(8):528–540
dant than LF in plasma, where it transports and delivers
iron to cells. Plasma LF concentrations increase during
the first and second trimesters of pregnancy. As LF is
released from neutrophils, this is interpreted as an indi-
cation of an inflammatory response.97 The stress hor-
mones epinephrine, norepinephrine, and dopamine form
complexes with TF and LF,98 reducing the iron-binding
capacity of these proteins.99,100
Genital tract infection and regulation of host
iron status
LF is produced constitutively by vaginal epithelial cells.101
The transcriptional activity of the LF gene is responsive
to estrogen in the reproductive system,102 and LF concen-
trations increase after menses.103 LF is released from the
secondary granules of neutrophils in response to vaginal
infections such as BV, which cause LF concentrations to
increase.104 LF in the genital tract has no known iron
transport function.96 Proteomic evaluations of cervico-
vaginal fluid have shown that this fluid contains an
abundance of major serum components, including tran-
sudated TF, which can be targeted by some pathogens for
iron release.105 LF forms stable complexes with iron at an
acid pH, whereas iron dissociates readily from TF at a pH
of 4 to 5, which may exist during inflammation, allowing
free iron to become available to pathogens.106 Another
proteomic profile of cervicovaginal fluid reported that
TF was increased twofold in samples from women with
PTB compared with samples from controls.107 LF can
bind lipopolysaccharide (LPS) and inhibit expression
of adhesion molecules necessary for recruitment of
immune cells at the site of inflammation.108 LPS is
expressed by some commensal pathogens associated with
PTB109,110 and, experimentally, LF supplementation sig-
nificantly improved the duration of gestation of LPS-
infected mice.111
The glycoprotein neutrophil gelatinase-associated
lipocalin (NGAL) is found in specific granules. It com-
plexes selectively with iron siderophores (high-affinity
iron-chelating substances) and sequesters iron.112 In a
mouse model, NGAL bound catecholate-type sidero-
phores used by E. coli, such as enterochelin, but not
the hydroxamate types such as aerobactin and fer-
richrome.113 Coinjection of E. coli and a siderophore to
which NGAL could not bind caused lethal infection in
lipocalin-deficient mice. In women with intra-amniotic
infection, NGAL expression in the trophoblast was
upregulated by interleukuin-1b, tumor necrosis factor-a,
and LPS.114 It was suggested that NGAL regulated the
availability of iron and thus prevented immune cell infil-
tration. In the genital tract, iron sequestration by mucosal
lipocalin 2 is probably complementary to the iron-
binding action of LF.115
533
General mechanisms of iron acquisition by pathogens
To overcome the host iron-withholding mechanisms out-
lined above, most pathogens use a number of uptake
mechanisms to acquire iron,116 although a few eliminate
genes encoding iron-dependent proteins.117 The elimina-
tion of genes that encode proteins is restricted mainly to
obligate parasites that do not require many biosynthetic
enzymes that use iron as a cofactor.118 Aerobic or faculta-
tive pathogens often secrete iron chelators, which scav-
enge host iron from iron-binding and heme-containing
proteins. Iron is transported across the outer membrane
into the periplasmic space, where it binds with a receptor
of an inner membrane ABC transporter and is subse-
quently transported into the bacterial cytoplasm.116 Iron
homeostasis in the pathogen is controlled by the ferric
uptake regulatory (Fur) protein.119 In the presence of suf-
ficient levels of iron, a Fur-iron complex prevents gene
transcription by binding to a specific Fur-box sequence.
Disruption of the fur gene can lead to decreased virulence
of the bacterial pathogen.
Bacterial biofilms have been described as environ-
ments specialized for long-term colonization of mucosal
surfaces.120 The formation of biofilms seems to require
a higher level of iron than is needed for bacterial
growth.121 Biofilms predispose infected individuals to
recurrent and treatment-resistant BV,122,123 which is asso-
ciated with the development of an adherent polymicro-
bial biofilm on the vaginal epithelium that contains
abundant G. vaginalis.
A better understanding of mechanisms that affect
iron acquisition by pathogens causing prenatal infections
is required, as this could have implications for maternal
iron supplementation.
Specific mechanisms of iron acquisition by pathogens
that cause maternal and neonatal infection
Gram-negative organisms. Most lactobacilli do not
require iron for growth, as they use manganese and
cobalt as cofactors for biological processes.124 Nonreli-
ance on iron may be a key factor favoring their pre-
dominance in the genital tract. Gram-negative bacteria,
causative agents of chorioamnionitis, utilize multiple
iron uptake mechanisms. G. vaginalis expresses a LF
receptor,27 directly binds hemoglobin but not TF, and
may utilize siderophores for iron extraction.125 Iron
acquisition functions have been confirmed in genomic
analysis of three different G. vaginalis strains.126 Neisser-
ia gonorrhoeae127 and Chlamydia trachomatis28 cause cer-
vicitis. N. gonorrhoeae has developed sophisticated
mechanisms for extracting iron from TF128 but also uti-
lizes iron from LF and hemoglobin.127 C. trachomatis is
an intracellular pathogen and, in vitro, cells not express-
534
ing ferroportin showed large elementary inclusion
bodies indicative of productive infection.85 Iron depri-
vation, however, may not be the primary mechanism in
immune control of C. trachomatis.129 On the contrary,
there is some evidence that low levels of iron affect
maturation of chlamydiae and could contribute to
persistence of infection or reactivation of dormant
infection.130
Gram-positive bacteria. There is far less information
available on iron uptake of Gram-positive bacteria.
M. hominis persists in low iron conditions.131 A
siderophore-dependent acquisition system has been
identified for Group B Streptococcus.132 Iron availability
seems to be of particular importance to Listeria mono-
cytogenes,119 which can colonize the genital tract and
produce biofilm when vaginal pH is raised to 6.5.133
This pathogen has a number of mechanisms for access-
ing iron, and it benefits from the iron-releasing actions
of catecholamines, which may explain its tropism for
the central nervous system in the neonate.18 L. monocy-
togenes growth in TF-loaded medium was enhanced by
the addition of norepinephrine at a physiological con-
centration found in blood during the development of
sepsis.
Parasites. Trichomonas vaginalis, which is associated
with a 40% increase in preterm low birth weight, is a
common infection, particularly among black women.134
Adherence to the epithelial cells of the urogenital tract is
an essential step in its pathogenesis. Iron is known to
substantially affect the activities of several metabolic
enzymes in T. vaginalis.135 Trichomonads, when grown in
low-iron medium supplemented with LF, had elevated
levels of adherence.136 This parasite mobilizes preformed
LF receptors to its surface and evokes gene expression
and protein synthesis of LF receptors in response to
falling levels of iron.29 This may enable the parasite to
respond to constantly fluctuating LF concentrations over
the menstrual cycle. Intracellular iron sources, such as
cytochromes, ferritin, and hemoglobin, are also likely
sources of iron for T. vaginalis.
Febrile malaria in humans is associated with high
blood hepcidin levels,137 and the resulting iron restriction
could explain resistance to the liver stage of malaria.138
There is little information available on iron regulation
and malarial infection during pregnancy. A cross-
sectional study at delivery reported that iron deficiency
was associated with decreased risk of placental para-
sitemia, especially in first pregnancies, supporting the
view that parasites causing placental malaria are iron
dependent.139 A placental histological study confirmed
that placental malaria was more frequent in iron-replete
women.140
Nutrition Reviews® Vol. 71(8):528–540
 IRON STATUS AND RISK OF INFECTION IN NEONATES
Factors affecting neonatal iron status
It is essential to consider the effects of maternal iron
supplementation and status on neonatal iron status, as the
influence of a baby’s iron status on the risk of infection
remains unclear. Maternal and neonatal iron hematologi-
cal biomarkers are not consistently correlated, but there is
evidence that severe maternal iron deficiency is associ-
ated with reduced neonatal iron stores.141 Most fetal iron
is accumulated against a concentration gradient in the
last trimester of pregnancy, and the fetus can regulate
iron uptake and transfer across the placenta,142 a process
in which maternal hepcidin is involved.88 In the fetus, as
in adults, liver iron regulates expression of hepcidin.143
Despite these regulatory mechanisms, many babies are
born anemic or with low iron stores, especially those with
low birth weight.11
The timing of events affecting iron status during
the first weeks of life could differentially influence the
risk of early- or late-onset neonatal sepsis. Sepsis is a
particular problem in preterm and very-low-birth-
weight babies (<1,500 g).35 Total body iron is low in
preterm infants, as 80% of iron in fetuses is acquired
during the third trimester of pregnancy.144 Growth-
restricted infants also have low total body iron stores
and are at risk of iron deficiency because of poor pla-
cental function and impaired placental iron trans-
port.145,146 Like preterm babies, they are susceptible to
oxidative damage by free radicals, despite their low iron
stores. This oxidative damage is enhanced by hemolysis
during congenital infection or by excess free iron
released from hemoglobin in erythrocytes following oxi-
dative stress.147,148 Free radicals may release even more
iron by mobilizing it from ferritin, leading to a cascade
of iron release and free radical production. Newborn
infants have lower levels of serum TF and high TF satu-
ration, which may result in elevated free iron. This low
iron-binding capacity correlates positively with the
capacity of blood to support bacterial growth.148 It is not
unusual for preterm infants to have abnormally high
serum ferritin concentrations, which may be related to
previous transfusions or inflammation.149 Therefore, any
protective effect of low iron stores at birth may be offset
by the availability and release of free iron that results
from these mechanisms.
Oral iron supplementation is generally not provided
to preterm and low-birth-weight babies in the first 4
weeks of life. The optimal dose and timing of commenc-
ing and ceasing iron supplementation in young infants
are unclear,150 and practice varies widely. Although iron
supplementation after the first 4 weeks of life is beneficial
in improving hemoglobin levels, it is uncertain whether
Nutrition Reviews® Vol. 71(8):528–540
this alters infection risk in early infancy in some of these
supplemented babies.
Neonatal iron status and bacterial sepsis
Since iron supplementation is not usually given during the
neonatal period, it is not possible to assess its impact on
infectious morbidity during this time. Many studies have
addressed this question in infants older than 1 month, and
the majority have been conducted in children older than 6
months.151,152 Over 30 years ago, a retrospective analysis
from New Zealand reported an increased incidence of
Gram-negative neonatal sepsis after intramuscular iron
administration, which decreased following discontinua-
tion of this practice.153 These data, drawn from a large
sample size, led to clinical concerns about the use of iron
interventions in the first few weeks of life. In vitro studies
using neonatal blood have implicated iron as enhancing
the growth of pathogens that cause neonatal sepsis,includ-
ing E. coli, Klebsiella pneumoniae, Pseudomonas aerugi-
nosa, Staphylococcus aureus, and L. monocytogenes.154,155
Altered fetal iron homeostasis following chorioamnionitis
was reported for neonates who had zinc protoporphyrin
values that were higher than expected for gestational age.
This suggested that diminished iron availability from fetal
hepatic iron stores was associated with prior chorioam-
nionitis, which may be related to maternal iron status.156
Neonatal iron status and malarial infection
Maternal iron deficiency has been associated with a
reduced risk of placental P. falciparum malaria.139,140
Maternal malaria at the end of pregnancy is an important
factor associated with time to the first episode of infant
malaria and survival in infancy157,158; in addition, it can
influence the infant immune response to malaria.159
Asymptomatic malaria is not uncommon in newborns,160
and symptomatic disease occurs as well. Under highly
endemic conditions, the prevalence of parasites and sple-
nomegaly is high in the first months of life, and young
infants are frequently susceptible to malaria.161–163 In
malarious areas, cord hemoglobin values below 14 g/dL,
which are indicative of fetal anemia, are commonly
reported and are associated with maternal iron defi-
ciency, placental malaria, and development of subsequent
infant anemia.164,165
In view of the potential risk of malaria, it is impor-
tant to consider how neonatal iron status might alter this
risk. It is conceivable that host iron status offers a protec-
tive effect from malarial infection. The effect may be
mediated by a lower labile iron pool in erythrocytes,
which could limit the growth of intracellular parasites,166
but direct experimental evidence of this is lacking. Two
recent detailed epidemiological studies indicated that iron
535
status predicted malaria risk in very young children.167,168
Tanzanian babies recruited at birth and who developed
iron deficiency during follow-up had significantly
decreased odds of subsequent parasitemia (23% decrease,
P < 0.01) and severe malaria (38% decrease, P = 0.04).167
Iron deficiency in these children was also associated with
60% lower all-cause mortality (P = 0.04) and 66% lower
malaria-associated mortality (P = 0.11). Similarly, iron
status predicted malaria risk in Malawian preschool chil-
dren, suggesting that iron deficiency protects against both
malaria parasitemia and clinical malaria in young chil-
dren.168 Those children with iron deficiency at baseline
had a lower incidence of malaria parasitemia and clinical
malaria during a year of follow-up (adjusted hazard ratios
0.55 [95%CI 0.41–0.74] and 0.49 [95%CI 0.33–0.73],
respectively). It has been proposed that iron status in
young infants regulates the risk of parasite superinfection
in a density-dependent manner governed by the iron regu-
latory hormone hepcidin.169
Although these studies provide striking evidence that
iron deficiency is related to a reduced risk of malaria and
reduced overall mortality, future investigations should
include blood cultures to assess the relative contribution of
malaria versus invasive bacterial diseases to mortality in
these young children.170 The data suggest that the interplay
between maternal and neonatal iron homeostasis could be
critically important for understanding potential risk of
infection in neonates and infants.
RESEARCH AND POLICY IMPLICATIONS
Use of iron to modulate infection risk in
pregnant women
Infectious morbidity related to the use of iron supple-
mentation could be potentially reduced by effective treat-
ment or antibiotic prophylaxis during prenatal care. A
good example is the current policy for use of antimalarial
drugs for intermittent preventive treatment of malaria in
pregnancy,171 although implementation is often inad-
equate.172 The importance of iron-infection interactions
may be particularly great among populations in low-
resource settings where health coverage is poor and the
prevalence of anemia is high. However, the lack of
adequate surveillance and treatment may make it difficult
to prevent an enhanced risk of infection caused by iron
supplementation in iron-replete women. Identification of
such women in resource-poor settings is also problematic
due to the effects of chronic inflammation on the most
readily available iron biomarkers.
A number of approaches to providing iron without
increasing the risk of infection are suggested, as listed
below.
536
Use of iron chelators. Iron chelators can be used to sup-
press the growth of intracellular bacteria resulting from
downregulation of ferroportin85 or to counteract resis-
tance to treatment caused by formation of bacterial
biofilm. Urinary tract E. coli strains form significantly less
biofilm in the presence of an iron chelator and form more
biofilm when iron is added to growth medium.173 The use
of chelators such as desferrioxamine E has been shown to
restore the activity of isoniazid against some mycobacte-
rial species174 and to reduce the severity of P. falciparum
malaria in children.175 Of interest are clinical agents that
interfere with microbial iron access, particularly nonsid-
erophore iron chelators such as deferiprone, deferasirox,
apotransferrin, and apolactoferrin.176 Such substances
could eventually be an adjunct to existing therapies. The
use and efficacy of iron chelators during pregnancy
require additional research, as most studies have not
examined these agents in pregnant women, except in
those with thalassemia, or have used pregnant animal
models.
Identification of vaccine targets. Six outer membrane iron
receptors have been identified as putative vaccine targets
to prevent urinary tract infection.177 Three of these recep-
tors protected mice from challenge with uropathogenic
E. coli strains. By targeting such receptors, it may be pos-
sible to disrupt the iron acquisition process and to neu-
tralize and opsonize pathogens.
Identification of iron-replete nonanemic women prior to
commencement of routine prenatal iron supplementation.
In nonanemic populations with low exposure to infec-
tion, biomarkers such as ferritin may have utility for
defining iron status.178 In areas with high exposure to
infection, there is a specific need for evaluation of iron
biomarkers as potential correlates of infection risk during
pregnancy along with a need to clarify their utility in
correlating iron status with inflammation in pregnancy. A
recent example of this is assessment of the utility of free
erythrocyte protoporphyrin in whole blood as a marker
of malaria risk in pregnancy.179 This biomarker has been
related to malaria risk in children under 3 years of age.180
Assessment of lactoferrin supplementation. The use of LF,
rather than ferrous iron, for prenatal supplementation
should be assessed because of the potential benefits of
LF’s bactericidal properties.181 Bovine LF has the same
efficacy as ferrous sulfate in restoring iron deposits in
iron-deficient pregnant women, with significantly fewer
gastrointestinal side effects.182
Provision of separate estimates for iron-replete and
-deficient populations. The provision of separate esti-
mates of neonatal infection and mortality rates among
Nutrition Reviews® Vol. 71(8):528–540
iron-replete and iron-deficient women in supplementa-
tion trials would help avoid the masking of potentially
contrasting risk profiles.
Assessment of nutrient levels and infection outcomes in
trials of intermittent versus daily iron supplementation.
While the focus of this review is on iron and infection,
many other nutrients have been increasingly linked to
infection and/or inflammation and anemic populations
may be deficient in these nutrients. A limitation of exist-
ing data sets and study designs is that confounding due to
the effects of multiple nutrients is not considered. This
issue should be scrutinized in future study designs.
Use of iron to modulate infection risk in infants
Breast milk is low in iron and contains the iron-binding
protein LF, which acts as an important component of
nonspecific host defense against pathogens.181 LF restricts
iron access to bacteria that cause neonatal sepsis.183,184 It
also reduces oxidative stress and free radical formation185
as well as the incidence of late-onset neonatal sepsis in
infants weighing less than 1,500 g at birth.186 Oral LF
supplementation should therefore reduce oxidative
stress,187 and its utility in reducing the risk of infection in
low-birth-weight infants by altering neonatal iron status
requires assessment.
CONCLUSION
Iron supplementation is required for some pregnant
women and finding a way to provide it safely is essential.
This review is the first to summarize the evidence that
pathogens that compromise mother, fetus, and infant are
reliant on access to iron, which increases their virulence
and may be more accessible as a result of iron supplemen-
tation. Host infection risk has not been adequately
addressed in clinical trials of iron supplementation that
have demonstrated the efficacy of supplementation in
reducing maternal anemia. Concerns about the safety of
maternal iron supplementation in populations with high
maternal and neonatal infection incidence should not be
ignored. The caution relates primarily to supplementa-
tion of iron-replete women. In order to address this
concern, a point-of-care test for the assessment of iron
status is urgently needed. Moreover, maternal anemia
may be secondary to infection, or other nutritional defi-
ciencies, and not be caused by iron deficiency. Provision
of adequate surveillance and treatment for infections will
reduce safety concerns, although this is currently only
realistic in connection with malaria control strategies in
pregnancy, which frequently have low coverage. The
clinical impact of maternal iron supplementation on
Nutrition Reviews® Vol. 71(8):528–540
other perinatal infections remains largely unknown, and
its possible influence on the risk of chorioamnionitis has
global relevance.
It is important that future research address alterna-
tive approaches to providing iron in the context of mater-
nal and infant infections. This will require a much
broader approach to nutritional profiling and biomarker
assessment in future study designs.
Acknowledgments
Funding. There was no external funding for this review.
LB is funded by the Max Elstein Trust. Researchers at
the University of Manchester receive support from the
Manchester Academic Health Science Centre and the
Central Manchester University Hospital NHS Trust. SG
is supported by National Institutes of Health (NIH)
research grant no. 1U01HD061234-01A1 funded by the
National Institute of Child Health and Human Develop-
ment and the NIH Office of Dietary Supplements.
Declaration of interest. The authors have no relevant
interests to declare.
REFERENCES
1. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? where? why?
Lancet. 2005;365:891–900.
2. Thaver D, Zaidi AK. Burden of neonatal infections in developing countries: a
review of evidence from community-based studies. Pediatr Infect Dis J.
2009;28(Suppl):S3–S9.
3. McGreal EP, Hearne K, Spiller OB. Off to a slow start: under-development of the
complement system in term newborns is more substantial following premature
birth. Immunobiology. 2012;217:176–186.
4. Raqib R, Alam DS, Sarker P, et al. Low birth weight is associated with altered
immune function in rural Bangladeshi children: a birth cohort study. Am J Clin
Nutr. 2007;85:845–852.
5. Palmer AC. Nutritionally mediated programming of the developing immune
system. Adv Nutr. 2011;2:377–395.
6. Basu S, Dewangan S, Shukla RC, et al. Thymic involution as a predictor of early-
onset neonatal sepsis. Paed Int Child Health. 2012;32:147–151.
7. Lawn JE, Cousens SN, Darmstadt GL, et al. 1 year after the Lancet Neonatal
Survival Series – was the call for action heard? Lancet. 2006;367:1541–1547.
8. Fernández-Gaxiola AC, De-Regil LM. Intermittent iron supplementation for
reducing anaemia and its associated impairments in menstruating women.
Cochrane Database Syst Rev. 2011;(12):CD009218.
9. World Health Organization. Weekly iron-folic acid supplementations (WIFS) in
women of reproductive age: its role in promoting optimal maternal and child
health. 2009; Available at: http://www.who.int/nutrition/publications/
micronutrients/weekly_iron_folicacid/en/. Accessed 10 May 2013.
10. Peña-Rosas JP, Viteri FE. Effects and safety of preventive oral iron or iron and
folic acid supplementation for women during pregnancy. Cochrane Database
Syst Rev. 2009;(4):CD004736.
11. Viteri FE. Iron endowment at birth: maternal iron status and other influences.
Nutr Rev. 2011;69(Suppl 1):S3–S16.
12. Beard JL. Iron biology in immune function, muscle metabolism and neural
functioning. J Nutr. 2001;131:568S–580S.
13. Cousens S, Blencowe H, Stanton C, et al. National, regional, and worldwide
estimates of stillbirth rates in 2009 with trends since 1995: a systematic analy-
sis. Lancet. 2011;377:1319–1330.
14. Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of
child mortality in 2008: a systematic analysis. Lancet. 2010;375:1969–1987.
15. Goldenberg RL, McClure EM, Saleem S, et al. Infection-related stillbirths. Lancet.
2010;375:1482–1490.
16. Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Engl J Med.
2010;362:529–535.
537
17. Loyevsky M, LaVaute T, Allerson CR, et al. An IRP-like protein from Plasmodium
falciparum binds to a mammalian iron-responsive element. Blood.
2001;98:2555–2562.
18. Coulanges V, Andre P, Ziegler O, et al. Utilization of iron-catecholamine com-
plexes involving ferric reductase activity in Listeria monocytogenes. Infect
Immun. 1997;65:2778–2785.
19. Eisenstein BI, Jones GW. The spectrum of infections and pathogenic mecha-
nisms of Escherichia coli. Adv Intern Med. 1988;33:231–252.
20. Mason WJ, Skaar EP. Assessing the contribution of heme-iron acquisition to
Staphylococcus aureus pneumonia using computed topography. PLoS ONE.
2009;4:e6668.
21. Chhibber S, Bajaj J. Polysaccharide-iron-regulated cell surface protein conju-
gate vaccine: its role in protection against Klebsiella pneumoniae-induced lobar
pneumonia. Vaccine. 1995;13:179–184.
22. Tsou CC, Chiang-Ni C, Lin YS, et al. An iron-binding protein, Dpr, decreases
hydrogen peroxide stress and protects Streptococcus pyogenes against multiple
stresses. Infect Immun. 2008;76:4038–4045.
23. Dill BD, Dessus-Babus S, Raulston JE. Identification of iron-responsive proteins
expressed by Chlamydia trachomatis reticulate bodies during intracellular
growth. Microbiology. 2009;155:210–219.
24. Sokol PA. Surface expression of ferripyochelin-binding protein is required for
virulence of Pseudomonas aeruginosa. Infect Immun. 1987;55:2021–2025.
25. Mevissen-Verhage EA, Marcelis JH, Vos MN, et al. Bifidobacterium, Bacteroides,
and Clostridium spp. in fecal samples from breast-fed and bottle-fed infants
with and without iron supplements. J Clin Microbiol. 1987;25:285–289.
26. Bliss JM, Basavegowda KP, Watson WJ, et al. Vertical and horizontal transmis-
sion of Candida albicans in very low birth weight infants using DNA fingerprint-
ing techniques. Pediatr Infect Dis J. 2008;27:231–235.
27. Jarosik GP, Land CB. Identification of a human lactoferrin-binding protein in
Gardnerella vaginalis. Infect Immun. 2000;68:3443–3447.
28. Rodrigues MM, Fernandes PA, Haddad JP, et al. Frequency of Chlamydia tra-
chomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Mycoplasma hominis
and Ureaplasma species in cervical samples. J Obstet Gynaecol. 2011;31:237–
241.
29. Lehker MW, Alderete JF. Iron regulates growth of Trichomonas vaginalis and the
expression of immunogenic trichomonad proteins. Mol Microbiol. 1992;6:123–
132.
30. Dimier IH, Bout DT. Interferon-gamma-activated primary enterocytes inhibit
Toxoplasma gondii replication: a role for intracellular iron. Immunology.
1998;94:488–495.
31. Ratledge C. Iron, mycobacteria and tuberculosis. Tuberculosis (Edinb).
2004;84:110–130.
32. Pfisterer C, Faber R, Horn LC. Chorioamnionitis-induced changes of fetal
extramedullar hematopoeisis in the second trimester of gestation. Is diagnosis
from fetal autopsy possible? Virchows Arch. 2005;446:150–156.
33. McClure E, Dudley DJ, Reddy UM, et al. Infectious causes of stillbirth: a clinical
perspective. Clin Obstet Gynecol. 2010;53:635–645.
34. Folgosa E, Gonzalez C, Osman NB, et al. A case control study of chorioamniotic
infection and histological choriamnionitis in stillbirth. APMIS. 1997;105:329–
336.
35. Zaidi AK, Thaver D, Ali SA, et al. Pathogens associated with sepsis in newborns
and young infants in developing countries. Pediatr Infect Dis J. 2009;28(Suppl
1):S10–S18.
36. Van Geertruyden JP, Thomas F, Erhart A, et al. The contribution of malaria in
pregnancy to perinatal mortality. Am J Trop Med Hyg. 2004;71:35–40.
37. Goldenberg RL, Andrews WW, Hauth JC. Choriodecidual infection and preterm
birth. Nutr Rev. 2002;60(Suppl 5):S19–S25.
38. Leitich J, Bodner-Adler B, Brunbauer M, et al. Bacterial vaginosis as a risk
factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol. 2003;
189:139–147.
39. Koumans E, Markowitz LE, Hogan V for the CDC BV Working Group. Indications
for therapy and treatment recommendations for bacterial vaginosis in non-
pregnant and pregnant women: a synthesis of data. Clin Infect Dis.
2002;35(Suppl 2):S152–S172.
40. Hay PE, Morgan DJ, Ison CA, et al. A longitudinal study of bacterial vaginosis
during pregnancy. Br J Obstet Gynaecol. 1994;101:1048–1053.
41. Donders GG, Van Calsteren K, Bellen G, et al. Predictive value for preterm birth
of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the
first trimester of pregnancy. Br J Obstet Gynaecol. 2009;116:1315–1324.
42. Romero R, Oyarzun E, Mazor M, et al. Meta-analysis of the relationship between
asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet
Gynecol. 1989;73:576–582.
43. Villar J, Gülmezoglu AM, de Onis M. Nutritional and antimicrobial interventions
to prevent preterm birth: an overview of randomized controlled trials. Obstet
Gynecol Surv. 1998;53:575–585.
44. Munn MB, Groome LJ, Atterbury JL, et al. Pneumonia as a complication of
pregnancy. J Matern Fetal Med. 1999;8:151–154.
45. Ormerod P. Tuberculosis in pregnancy and the puerperium. Thorax.
2001;54:494–499.
538
46. Brabin BJ, Romagosa C, Abdelgalil S, et al. The sick placenta – the role of
malaria. Placenta. 2004;25:359–378.
47. Hammerschlag MR. Chlamydial infections. J Pediatr. 1989;114:727–734.
48. Valkenburg-van den Berg AW, Houtman-Roelofsen RL, Oostvogel PM, et al.
Timing of Group B streptococcus screening in pregnancy: a systematic review.
Gynecol Obstet Invest. 2010;69:174–183.
49. Sterkers Y, Pratlong F, Albaba S, et al. Novel interpretation of molecular diag-
nosis of congenital toxoplasmosis according to gestational age at the time of
maternal infection. J Clin Microbiol. 2012;50:3944–3951.
50. Senior K. Antenatal screening for group B streptococcus. Lancet Infect Dis.
2012;12:589–590.
51. Blatt AJ, Lieberman JM, Hoover DR, et al. Chamydial and gonococcal testing
during pregnancy in the United States. Am J Obstet Gynecol. 2012;207:e1–e8.
52. Rasmussen KM. Is there a causal relationship between iron deficiency or iron-
deficiency anemia and weight at birth, length of gestation and perinatal mor-
tality? J Nutr. 2001;131:S590–S601.
53. McCaw-Binns A, Greenwood R, Ashley D, et al. Antenatal and perinatal care in
Jamaica: do they reduce perinatal death rates? Paediatr Perinat Epidemiol.
1994;8(Suppl 1):86–97.
54. Christian P, West KP, Khatry SK, et al. Effects of maternal micronutrient supple-
mentation on fetal loss and infant mortality: a cluster-randomized trial in
Nepal. Am J Clin Nutr. 2003;78:1194–1202.
55. Hemminki E, Rimpelä U. A randomized comparison of routine versus selective
iron supplementation during pregnancy. J Am Coll Nurs. 1991;10:3–10.
56. Ziaei S, Norrozi M, Faghihzadeh S, et al. A randomised placebo-controlled trial
to determine the effect of iron supplementation on pregnancy outcome in
pregnant women with haemoglobin ⱖ13.2 g/dL. Br J Obstet Gynaecol.
2007;1145:684–688.
57. Zeng L, Dibley MJ, Cheng Y, et al. Impact of micronutrient supplementation
during pregnancy on birth weight, duration of gestation, and perinatal mortal-
ity in rural western China: double blind cluster randomised controlled trial. BMJ.
2008;337:a2001.
58. Titaley CR, Dibley MJ, Roberts CL, et al. Iron and folic acid supplements and
reduced early neonatal deaths in Indonesia. Bull World Health Organ.
2010;88:500–508.
59. Titaley CR, Dibley MJ, Roberts CL, et al. Combined iron/folic acid supplements
and malaria prophylaxis reduce neonatal mortality in 19 sub-Saharan coun-
tries. Am J Clin Nutr. 2010;92:235–243.
60. Preziosi P, Prual A, Galan P, et al. Effect of iron supplementation on the iron
status of pregnant women: consequences for newborns. Am J Clin Nutr.
1997;66:1178–1182.
61. Christian P, Shrestha J, LeClerq SC, et al. Supplementation with micronutrients
does not further improve the hematologic status of pregnant women in rural
Nepal. J Nutr. 2003;133:3492–3498.
62. Dibley MJ, Titaley CR, d’Este C, et al. Iron and folic acid supplements in preg-
nancy improve child survival in Indonesia. Am J Clin Nutr. 2012;95:220–230.
63. Ronsmans C, Fisher DJ, Osmond C, et al. for the Maternal Micronutrient
Supplementation Group. Multiple micronutrient supplementation during
pregnancy in low-income countries: a meta-analysis of effects on stillbirths and
on early and late neonatal mortality. Food Nutr Bull. 2009;30(Suppl 4):S547–
S555.
64. Shankar AH, Jahari AB, Sebayang SK, et al. Effect of maternal multiple micro-
nutrient supplementation on fetal loss and infant death in Indonesia: a double-
blind cluster-randomised trial. Lancet. 2008;371:215–227.
65. Peña Rosas JP, De-Regil LM, Dowswell T, et al. Intermittent oral iron
supplementation during pregnancy. Cochrane Database Syst Rev. 2012;(7):
CD009997.
66. Fleming AF, Ghatoura GB, Harrison KA, et al. The prevention of anaemia in
pregnancy in primigravidae in the guinea savanna of Nigeria. Ann Trop Med
Parasitol. 1986;80:211–233.
67. Menendez C, Todd J, Alonso PL, et al. The effects of iron supplementation
during pregnancy, given by traditional birth attendants, on the prevalence of
anaemia and malaria. Trans R Soc Trop Med Hyg. 1994;88:590–593.
68. Nacher M, McGready R, Stepniewska K, et al. Haematinic treatment of anaemia
increases the risk of Plasmodium vivax malaria in pregnancy. Trans R Soc Trop
Med Hyg. 2003;97:273–276.
69. Byles AB, D’sa A. Reduction of reaction due to iron dextran infusion using
chloroquine. BMJ. 1970;3:625–627.
70. Oppenheimer SJ, MacFarlane SB, Moody JB, et al. Total dose of iron infusion,
malaria and pregnancy in Papua New Guinea. Trans R Soc Trop Med Hyg.
1986;80:818–822.
71. Garn SM, Ridella SA, Petzold AS, et al. Maternal hematological levels and preg-
nancy outcomes. Semin Perinatol. 1981;5:155–162.
72. Murphy JF, O’Riordan J, Newcombe RG, et al. Relation of haemoglobin levels in
first and second trimesters to outcome of pregnancy. Lancet. 1986;327:992–
995.
73. Zhou L-M, Yang W-W, Hua J-Z, et al. Relation of hemoglobin measured at dif-
ferent times in pregnancy to preterm birth and low birth weight in Shanghai,
China. Am J Epidemiol. 1998;148:998–1006.
Nutrition Reviews® Vol. 71(8):528–540
 74. Scanlon KS, Yip R, Schieve LA, et al. High and low hemoglobin levels during
pregnancy: differential risks for preterm birth and small for gestational age.
Obstet Gynecol. 2000;96:741–748.
75. Stephansson O, Dickman PW, Johansson A, et al. Maternal hemoglobin concen-
tration during pregnancy and risk of stillbirth. JAMA. 2000;284:2611–2617.
76. Brabin BJ, Hakimi M, Pelletier D. An analysis of anemia and pregnancy-related
maternal mortality. J Nutr. 2001;131:S604–S614.
77. Casanueva E, Viteri FE, Mares-Galindo M, et al. Weekly iron as a safe alternative
to daily supplementation for nonanemic pregnant women. Arch Med Res.
2006;37:674–682.
78. Steer P, Alam MA, Wadsworth J, et al. Relation between maternal haemoglobin
concentration and birth weight in different ethnic groups. BMJ. 1995;310:489–
491.
79. Ribot B, Aranda N, Viteri F, et al. Depleted iron stores without anaemia early in
pregnancy carries increased risk of lower birthweight even when supple-
mented daily with moderate iron. Hum Reprod. 2012;27:1260–1266.
80. Yip R. Significance of an abnormally low or high hemoglobin concentration
during pregnancy: special consideration of iron nutrition. Am J Clin Nutr.
2000;72(Suppl):S272–S279.
81. Viteri FE, Casanueva E, Tolentino MC, et al. Antenatal iron supplements con-
sumed daily produce oxidative stress in contrast to weekly supplementation in
Mexican non-anemic women. Reprod Toxicol. 2012;34:125–132.
82. Scholl TO. High third-trimester ferritin concentration: associations with very
preterm delivery, infection, and maternal nutritional status. Obstet Gynecol.
1998;92:161–166.
83. Verstraelen H, Delanghe J, Roelens K, et al. Subclinical iron deficiency is a strong
predictor of bacterial vaginosis in early pregnancy. BMC Infect Dis. 2005;5:55.
84. Kortman GA, Boleij A, Swinkels DW, et al. Iron availability increases the patho-
genic potential of Salmonella typhimurium and other enteric pathogens at the
intestinal epithelial interface. PLoS ONE. 2012;7:e29968.
85. Paradkar PN, De Domenico I, Durchfort N, et al. Iron depletion limits intracellu-
lar bacterial growth in macrophages. Blood. 2008;112:866–874.
86. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta.
2012;1823:1434–1443.
87. Evastatiev R, Gasche C. Iron sensing and signaling. Gut. 2012;61:933–952.
88. Young MF, Griffin J, Pressman E, et al. Maternal hepcidin is associated with
placental transfer of iron derived from dietary heme and nonheme sources. J
Nutr. 2012;142:33–39.
89. Rehu M, Punnonen K, Ostland V, et al. Maternal serum hepcidin is low at term
and independent of cord blood iron status. Eur J Haematol. 2010;85:345–352.
90. Finberg KE. Unraveling mechanisms regulating systemic iron homeostasis.
Hematology Am Soc Hematol Educ Program. 2011;2011:532–537.
91. Nairz M, Theurl I, Schroll A, et al. Absence of functional Hfe protects mice from
invasive Salmonella enteritica serovar Typhimurium infection via induction of
lipocalin-2. Blood. 2009;114:3642–3651.
92. Liu XB, Hill P, Haile DJ. Role of the ferroportin iron-responsive element in iron
and nitric oxide dependent gene regulation. Blood Cells Mol Dis. 2002;29:315–
326.
93. Gyarmati B, Szabó E, Szalay B, et al. Serum maternal hepcidin levels 3 days after
delivery are higher compared to those measured at parturition. J Obstet Gynae-
col Res. 2011;37:1620–1624.
94. Byrd TF, Horwitz MA. Interferon gamma-activated human monocytes down-
regulate transferrin receptors and inhibit the intracellular multiplication of
Legionella pneumophila by limiting the availability of iron. J Clin Invest.
1989;83:1457–1465.
95. Boelart JR, Vandecasteele SJ, Appelberg R, et al. The effect of the host’s iron
status on tuberculosis. J Infect Dis. 2007;195:1745–1753.
96. Baker EN, Baker HM, Kidd RD. Lactoferrin and transferrin: functional variations
on a common structural framework. Biochem Cell Biol. 2002;80:27–34.
97. Rebelo I, Carvalho-Guerra F, Pereira-Leite L, et al. Lactoferrin as a sensitive
blood marker of neutrophil activation in normal pregnancies. Eur J Obstet
Gynecol. 1995;62:189–194.
98. Freestone PP, Lyte M, Neal CP, et al. The mammalian neuroendocrine hormone
norepinephrine supplies iron for bacteria growth in the presence of transferrin
or lactoferrin. J Bacteriol. 2000;182:6091–6098.
99. Sandrini SM, Shergill R, Woodward J, et al. Elucidation of the mechanism by
which catecholamine stress hormones liberate iron from the innate immune
defence proteins transferrin and lactoferrin. J Bacteriol. 2010;192:587–594.
100. Lyte M, Vulchanova L, Brown DR. Stress at the intestinal surface: catechola-
mines and mucosa-bacteria interactions. Cell Tissue Res. 2011;343:23–32.
101. Teng CT, Beard C, Gladwell W. Differential expression and estrogen response of
lactoferrin gene in the female reproductive tract of mouse, rat, and hamster.
Biol Reprod. 2002;67:1439–1449.
102. Teng CT. Factors regulating lactoferrin gene expression. Biochem Cell Biol.
2006;84:263–267.
103. Cohen MS, Britigan BE, French M, et al. Preliminary observations on lactoferrin
secretion in human vaginal mucus: variation during the menstrual cycle, evi-
dence of hormonal regulation, and implications for infection with Neisseria
gonorrhoeae. Am J Obstet Gynecol. 1987;157:1122–1125.
Nutrition Reviews® Vol. 71(8):528–540
104. Goldenberg RL, Andrews WW, Guerrant RL, et al. for the National Institute of
Child Health and Human Development Maternal-Fetal Medicine Units Network.
The Preterm Prediction Study: cervical lactoferrin concentration, other markers
of lower genital tract infection, and preterm birth. Am J Obstet Gynecol.
2000;182:631–635.
105. Tang LJ, De Seta F, Odreman F, et al. Proteomic analysis of human cervical-
vaginal fluids. J Proteome Res. 2007;6:2874–2883.
106. Koczura R, Kaznowski A. The Yersinia high-pathogenicity island and iron
uptake systems in clinical isolates of Escherichia coli. J Med Microbiol.
2003;52:637–642.
107. Pereira L, Reddy AP, Jacob T, et al. Identification of novel protein biomarkers of
preterm birth in human cervical-vaginal fluid. J Proteome Res. 2007;6:1269–
1276.
108. Legrand D, Mazurier J. A critical review of the roles of host lactoferrin in immu-
nity. Biometals. 2010;23:365–376.
109. Aroutcheva A, Ling Z, Faro S. Prevotella bivia as a source of lipopolysaccharide in
the vagina. Anaerobe. 2008;14:256–260.
110. Otsuki K, Yoda A, Toma Y, et al. Lactoferrin and interleukin-6 interactions in
amniotic infection. Adv Exp Med Biol. 1998;443:267–271.
111. Otsuki K, Yakuwa K, Sawada M, et al. Recombinant lactoferrin has preventive
effects on lipopolysaccharide-induced preterm delivery and production of
inflammatory cytokines in mice. J Perinat Med. 2005;33:320–323.
112. Flo TH, Smith KD, Sato S, et al. Lipocalin 2 mediates an innate immune response
to bacterial infection by sequestrating iron. Nature. 2004;432:917–921.
113. Miethke M, Skerra A. Neutrophil gelatinase-associated lipocalin expresses anti-
microbial activity by interfering with L-norepinephrine-mediated bacterial iron
acquisition. Antimicrob Agents Chemother. 2010;54:1580–1589.
114. Tadesse S, Luo G, Park JS, et al. Intra-amniotic infection upregulates neutrophil
gelatinase-associated lipocalin (NGAL) expression at the maternal-fetal inter-
face at term: implications for infection-related preterm birth. Reprod Sci.
2011;18:713–722.
115. Goetz DH, Holmes MA, Borregaard N, et al. The neutrophil lipocalin NGAL is a
bacteriostatic agent that interferes with siderophore-mediated iron acquisi-
tion. Mol Cell. 2002;10:1033–1043.
116. Brown JS, Holden DW. Iron acquisition by gram-positive bacterial pathogens.
Microbes Infect. 2002;4:1149–1156.
117. Garcia EC, Brumbaugh AR, Mobley HL. Redundancy and specificity of Escheri-
chia coli iron acquisition systems during urinary tract infection. Infect Immun.
2011;79:1225–1235.
118. Posey JE, Gherardini FC. Lack of a role for iron in the Lyme disease pathogen.
Science. 2000;288:1651–1653.
119. McLaughlin HP, Hill C, Gahan CG. The impact of iron on Listeria monocytogenes;
inside and outside the host. Curr Opin Biotechnol. 2011;22:194–199.
120. Brown MR, Allison DG, Gilbert P. Resistance of bacterial biofilms to antibiotics:
a growth-related effect? J Antimicrob Chemother. 1988;22:777–780.
121. Singh PK, Parsek MR, Greenberg EP, et al. A component of innate immunity
prevents bacterial biofilm development. Nature. 2002;417:552–555.
122. Swidsinski A, Mendling W, Loening-Baucke V, et al. Adherent biofilms in bac-
terial vaginosis. Obstet Gynecol. 2005;106:1013–1023.
123. Verstraelen H, Swidsinski A. The biofilm in bacterial vaginosis: implications for
epidemiology, diagnosis and treatment. Current Opin Infect Dis. 2013;26:86–
89.
124. Macklaim JM, Gloor GB, Anukam KC, et al. At the crossroads of vaginal health
and disease, the genome sequence of Lactobacillus iners AB-1. Proc Natl Acad
Sci U S A. 2011;108:4688–4695.
125. Jarosik GP. Identification of a Gardnerella vaginalis hemoglobin-binding
protein. Curr Microbiol. 2001;42:49–52.
126. Yeoman CJ, Yildirim S, Thomas SM, et al. Comparative genomics of Gardnerella
vaginalis strains reveals substantial differences in metabolic and virulence
potential. PLoS One. 2010;5:e12411.
127. Rohde KH, Dyer DW. Mechanisms of iron acquisition by the human pathogens
Neisseria meningitidis and Neisseria gonorrhoeae. Front Biosci. 2003;8:1186–
1218.
128. Noinaj N, Easley NC, Oke M, et al. Structural basis for iron piracy by pathogenic
Neisseria. Nature. 2012;483:53–58.
129. Igietseme JU, Ananaba GA, Candal DH, et al. Immune control of chlamydial
growth in the human epithelial cell line RT4 involves multiple mechanisms that
include nitric oxide induction, tryptophan catabolism and iron deprivation.
Microbiol Immunol. 1998;42:617–625.
130. Al-Younes HM, Rudel T, Brinkmann V, et al. Low iron availability modulates
the course of Chlamydiae pneumoniae infection. Cell Microbiol. 2001;3:427–
437.
131. Vancini RG, Benchimol M. Entry and intracellular location of Mycoplasma
hominis in Trichomonas vaginalis. Arch Microbiol. 2008;189:7–18.
132. Clancy A, Loar JW, Speziali CD, et al. Evidence for siderophore-dependent iron
acquisition in group B streptococcus. Mol Microbiol. 2006;59:707–721.
133. Borges SF, Silva JG, Teixeira PC. Survival and biofilm formation of Listeria mono-
cytogenes in simulated vaginal fluid: influence of pH and strain origin. FEMS
Immunol Med Microbiol. 2011;62:315–320.
539
134. Cotch MF, Pastorek JG, Nugent RP, et al. Trichomonas vaginalis associated with
low birth weight and preterm delivery. The Vaginal Infections and Prematurity
Study Group. Sex Transm Dis. 1997;24:353–360.
135. Leitsch D, Kolarich D, Duchêne M. The flavin inhibitor diphenyleneiodonium
renders Trichomonas vaginalis resistant to metronidazole, inhibits thioredoxin
reductase and flavin reductase, and shuts off hydrogenosomal enzymatic path-
ways. Mol Biochem Parasitol. 2010;171:17–24.
136. Peterson KM, Alderete JF. Iron uptake and increased intracellular enzyme activ-
ity follow host lactoferrin binding by Trichomonal vaginalis receptors. J Exp
Med. 1984;160:398–410.
137. De Mast Q, Nadjm B, Reyburn H, et al. Assessment of urinary concentrations of
hepcidin provides novel insight into disturbances in iron homeostasis during
malarial infection. J Infect Dis. 2009;199:253–262.
138. Portugal S, Carret C, Recker M, et al. Host-mediated regulation of superinfection
in malaria. Nat Med. 2011;17:732–737.
139. Kabyemela ER, Fried M, Kurtis JD, et al. Decreased susceptibility to Plasmodium
falciparum infection in pregnant women with iron deficiency. J Infect Dis.
2008;198:163–166.
140. Senga EL, Harper G, Koshy G, et al. Reduced risk for placental malaria in iron
deficient women. Malar J. 2011;10:47.
141. Choi JW, Kim CS, Pai SH. Erythopoietic activity and soluble transferrin receptor
levels in neonates and maternal blood. Acta Paediatr. 2000;89:675–679.
142. McArdle HJ, Lang C, Hayes H, et al. Role of the placenta in regulation of fetal iron
status. Nutr Rev. 2011;69(Suppl 1):S17–S22.
143. Balesaria S, Hanif R, Salama MF, et al. Fetal iron levels are regulated by maternal
and fetal Hfe genotype and dietary iron. Haematologica. 2012;97:661–669.
144. Baker RD, Greer FR, and the Committee on Nutrition American Academy of
Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency
anemia in infants and young children (0–3 years of age). Pediatrics.
2010;126:1040–1050.
145. Chockalingam UM, Murphy E, Ophoven JC, et al. Cord transferrin and ferritin
values in newborn infants at risk for prenatal uteroplacental insufficiency and
chronic hypoxia. J Pediatr. 1987;111:283–286.
146. Siddappa AM, Rao R, Long JD, et al. The assessment of newborn iron stores at
birth: a review of the literature and standards for ferritin concentrations. Neo-
natology. 2007;92:73–82.
147. Evans PJ, Evans R, Kovar IZ, et al. Bleomycin-detectable iron in the plasma of
premature and full-term neonates. FEBS Lett. 1992;303:210–212.
148. Buonocore G, Perrone S, Bracci R. Free radicals and brain damage in the
newborn. Biol Neonate. 2001;79:180–186.
149. Rao R, Georgieff MK. Iron therapy for preterm infants. Clin Perinatol.
2009;36:27–42.
150. Mills RJ, Davies MW. Enteral iron supplementation in preterm and low birth
weight infants. Cochrane Database Syst Rev. 2012;(3):CD005095.
151. Ojukwu JU, Okebe JU, Yahav D, et al. Oral iron supplementation for preventing
and treating anaemia among children in malaria-endemic areas. Cochrane
Database Syst Rev. 2011;(10): CD006589.
152. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J
Nutr. 2001;131:S616–S633.
153. Barry DM, Reeve AW. Increased incidence of gram-negative neonatal sepsis
with intramuscular iron administration. Pediatrics. 1977;60:908–912.
154. Levine RL, Lemons JA. Letter: Concentrations of serum iron in relation to infec-
tion in the neonate. J Pediatr. 1975;87:331–332.
155. Becroft DM, Dix MR, Farmer K. Intramuscular iron dextran and susceptibility of
neonates to bacterial infections. In vitro studies. Arch Dis Child. 1977;52:778–
781.
156. Juul S, Zerzan JC, Strandjord TP, et al. Zinc protoporphyrin/heme as an indicator
of iron status in NICU patients. J Pediatr. 2003;142:273–278.
157. Bardaji A, Sigauque B, Sanz S, et al. Impact of malaria at the end of pregnancy
on infant mortality and morbidity. J Infect Dis. 2011;203:691–699.
158. Schwarz NG, Adegnika AA, Breitling LP, et al. Placental malaria increases
malaria risk in the first 30 months of life. Clin Infect Dis. 2008;47:1017–1025.
159. Malhotra I, Dent A, Mungai P, et al. Can prenatal malaria exposure produce an
immune tolerant phenotype?: A prospective birth cohort study in Kenya. PLoS
Med. 2009;6:e1000116.
160. Hartman TK, Rogerson SJ, Fischer PR. The impact of maternal malaria on new-
borns. Ann Trop Paediatr. 2010;30:271–282.
161. Brabin BJ. An analysis of malaria parasite rates in infants: 40 years after Mac-
donald. Trop Dis Bull. 1990;87:R1–R21.
540
162. Riley EM, Wagner GE, Akanmori BD, et al. Do maternally acquired antibodies
protect infants from malaria infection? Parasite Immunol. 2001;23:51–59.
163. D’Alessandro U, Ubben D, Hamed K, et al. Malaria in infants aged less than six
months – is it an area of unmet medical need? Malar J. 2012;11:400.
164. Le Cessie S, Verhoeff FH, Mengistie G, et al. Changes in haemoglobin levels in
infants in Malawi: effect of low birth weight and fetal anaemia. Arch Dis Child
Fetal Neonatal Ed. 2002;86:F182–F187.
165. Brabin BJ, Kalanda BF, Verhoeff FH, et al. Risk factors for fetal anaemia in a
malarious area of Malawi. Ann Trop Paediatr. 2004;24:311–321.
166. Prus E, Fibach E. The labile iron pool in human erythroid cells. Br J Haematol.
2008;142:301–307.
167. Gwamaka M, Kurtis JD, Sorensen BE, et al. Iron deficiency protects against
severe Plasmodium falciparum malaria and death in young children. Clin Infect
Dis. 2012;54:1137–1144.
168. Jonker FA, Calis JC, Boele van Hensbroek MB, et al. Iron status predicts malaria
risk in Malawian preschool children. PLoS One. 2012;7:e42670.
169. Portugal S, Drakesmith H, Mota MM. Superinfection in malaria: Plasmodium
shows its iron will. EMBO Rep. 2011;12:1233–1242.
170. Maltha J, Jacobs J. Iron deficiency and malaria mortality: possible implication of
invasive bacterial diseases. Clin Infect Dis. 2012;55:748.
171. Ter Kuile FO, Van Eijk AM, Filler SJ. Effect of sulfadoxine-pyrimethamine resis-
tance on the efficacy of preventive therapy for malaria control during preg-
nancy. JAMA. 2007;297:2603–2616.
172. Van Eijk AM, Hill J, Alegana VA, et al. Coverage of malaria protection in pregnant
women in sub-Saharan Africa: a synthesis and analysis of national survey data.
Lancet Infect Dis. 2011;11:190–207.
173. Hancock V, Ferrières L, Klemm P. The ferric yersiniabactin uptake receptor FyuA
is required for efficient biofilm formation by urinary tract infectious Escherichia
coli in human urine. Microbiology. 2008;154:167–175.
174. Ishida S, Arai M, Niikawa H, et al. Inhibitory effect of cyclic trihydroxamate
siderophore, desferrioxamine E, on the biofilm formation of Mycobacterium
species. Biol Pharm Bull. 2011;34:917–920.
175. Gordeuk VR, Loyevsky M. Antimalarial effects of iron chelators. Adv Exp Med
Biol. 2002;509:251–257.
176. Weinberg ED. Iron availability and infection. Biochim Biophys Acta.
2009;1790:600–605.
177. Alteri CJ, Hagan EC, Sivick KE, et al. Mucosal immunization with iron receptor
antigens protects against urinary tract infection. PLoS Pathog. 2009;5:
e1000586.
178. Lao TT, Tam K-F, Chan LY. Third trimester iron status and pregnancy outcome in
non-anaemic women; pregnancy unfavourably affected by maternal iron
excess. Hum Reprod. 2000;15:1843–1848.
179. Senga E, Koshy G, Brabin BJ. Zinc erythrocyte protoporphyrin as a marker of
malaria risk in pregnancy – a retrospective cross-sectional and longitudinal
study. Malar J. 2012;11:249.
180. Sazawal S, Black RE, Ramsan M, et al. Effects of routine prophylactic supple-
mentation with iron and folic acid on admission to hospital and mortality in
preschool children in a high malaria transmission setting: community-based,
randomised, placebo-controlled trial. Lancet. 2006;367:133–143. Erratum in:
Lancet 2006;367:302.
181. Actor JK, Hwang S-A, Kruzel ML. Lactoferrin as a natural immune modulator.
Curr Pharm Des. 2009;15:1956–1973.
182. Nappi C, Tommaselli GA, Morra I, et al. Efficacy and tolerability of oral bovine
lactoferrin compared to ferrous sulfate in pregnant women with iron deficiency
anemia: a prospective controlled randomized study. Acta Obstet Gynecol
Scand. 2009;88:1031–1035.
183. Nibbering PH, Ravensbergen E, Welling MM, et al. Human lactoferrin and pep-
tides are highly effective against infections with antibiotic-resistant bacteria.
Infect Immun. 2001;69:1469–1476.
184. Manzoni P, Rinaldi M, Cattani S, et al. Bovine lactoferrin supplementation for
prevention of late-onset sepsis in very low-birth-weight neonates: a ran-
domised trial. JAMA. 2009;302:1421–1428.
185. Ward PP, Conneely OM. Lactoferrin: role in iron homeostasis and host defence
against microbial infection. Biometals. 2004;17:203–208.
186. Pammi M, Abrams SA. Oral lactoferrin for the prevention of sepsis and necro-
tizing enterocolitis in preterm infants. Cochrane Database Syst Rev.
2011;(10):CD007137.
187. Tarnow-Mordi W, Isaacs D, Dutta S. Adjunctive immunologic interventions in
neonatal sepsis. Clin Perinatol. 2010;37:481–499.
Nutrition Reviews® Vol. 71(8):528–540
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