Iron status during pregnancy: setting the stage for mother and
infant1– 4
Theresa O Scholl
ABSTRACT
Supplementation with iron is generally recommended during preg-
nancy to meet the iron needs of both mother and fetus. When detected
early in pregnancy, iron deficiency anemia (IDA) is associated with
a 쏜 2-fold increase in the risk of preterm delivery. Maternal anemia
when diagnosed before midpregnancy is also associated with an
increased risk of preterm birth. Results of recent randomized clinical
trials in the United States and in Nepal that involved early supple-
mentation with iron showed some reduction in risk of low birth
weight or preterm low birth weight, but not preterm delivery. During
the 3rd trimester, maternal anemia usually is not associated with
increased risk of adverse pregnancy outcomes and may be an indi-
cator of an expanded maternal plasma volume. High levels of he-
moglobin, hematocrit, and ferritin are associated with an increased
risk of fetal growth restriction, preterm delivery, and preeclampsia.
While iron supplementation increases maternal iron status and
stores, factors that underlie adverse pregnancy outcome are consid-
ered to result in this association, not iron supplements. On the other
hand, iron supplements and increased iron stores have recently been
linked to maternal complications (eg, gestational diabetes) and in-
creased oxidative stress during pregnancy. Consequently, while iron
supplementation may improve pregnancy outcome when the mother
is iron deficient it is also possible that prophylactic supplementation
may increase risk when the mother does not have iron deficiency or
IDA. Anemia and IDA are not synonymous, even among low-
income minority women in their reproductive years. Am J Clin
Nutr 2005;81(suppl):1218S–22S.
KEY WORDS Anemia, iron deficiency, ferritin, oxidative
stress, preterm delivery, low birth weight, gestational diabetes, iron,
supplementation, pregnancy
INTRODUCTION
Anemia, as determined by low hemoglobin or hematocrit, is
common among women in their reproductive years in particular
if the women are poor, pregnant, and members of an ethnic
minority. Until recently, it was assumed that anemia during preg-
nancy had few untoward sequelae. During the past few years, the
relation between anemia early in pregnancy and an increased risk
of preterm delivery has been suggested. Likewise, the relation of
adverse pregnancy outcomes with high hemoglobin and in-
creased iron stores has been documented. However, the risks and
benefits of prophylactic iron supplementation in pregnant
women who are not iron deficient remains a source of contro-
versy.
1218S Am J Clin Nutr 2005;81(suppl):1218S–22S. Printed in USA. © 2005 American Society for Clinical Nutrition
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PREVALENCE AND ETIOLOGY OF ANEMIA AND
IRON DEFICIENCY IN WOMEN
Iron deficiency is the most commonly recognized nutritional
deficit in either the developed or the developing world. During
their reproductive years women are at risk of iron deficiency due
to blood loss from menstruation, in particular that 10% who
suffer heavy losses (쏜80 mL/mo). Contraceptive practice also
plays a part—the intrauterine devices increases menstrual blood
loss by 30%–50% while oral contraceptives have the opposite
effect. Pregnancy is another factor. During pregnancy there is a
significant increase in the amount of iron required to increase the
red cell mass, expand the plasma volume and to allow for the
growth of the fetal-placental unit. Finally, there is diet. Women
in their reproductive years often have a dietary iron intake that is
too low to offset losses from menstruation and the increased iron
requirement for reproduction (1). Consequently, the overall
prevalence of iron deficiency in non-pregnant women of repro-
ductive age in the United States, 9%–11%, is higher than at other
ages apart from infancy. The prevalence of IDA in the same age
group is 2%–5%. Prevalence of iron deficiency and IDA is in-
creased 2-fold or more for those women who are minorities,
below the poverty level or with 쏝 12 y of education. Risk is also
increased with parity—nearly 3-fold higher for women with 2–3
children and nearly 4-fold greater for women with 4 or more
children, thus implicating pregnancy (2).
It is estimated that 쏝 50% of women do not have adequate iron
stores for pregnancy (1, 3). Because the iron required for preg-
nancy (3– 4 mg/d) is substantial, risk of iron deficiency and IDA
should increase with gestation. However, the prevalence of ane-
mia and IDA in pregnant women from the United States is not
well defined but must be substantial, particularly among the poor.
During pregnancy, anemia increases 쏜 4-fold from the 1st to the
3rd trimester in the low-income women monitored as part of
pregnancy nutritional surveillance by the CDC (3). In the Cam-
den Study where the cohort is mostly minority, current data
(2000 –2004) suggest that the prevalence of anemia increases 쏜
1
From the Department of Obstetrics and Gynecology, The University of
Medicine and Dentistry of New Jersey - SOM, Stratford, New Jersey 08084.
2
Presented at the conference “Women and Micronutrients: Addressing the
Gap Throughout the Life Cycle,” held in New York, NY, June 5, 2004.
3
Supported by HD18269, HD38329, and ES07437 from the National
Institutes of Health.
4
Address reprint requests and correspondence to Theresa O Scholl,
UMDNJ-SOM, Department of Ob/Gyn, Science Center, Suite 390, Stratford,
NJ 08104. E-mail: scholl@umdnj.edu.
 MATERNAL ANEMIA AND HIGH HEMOGLOBIN
FIGURE 1. Anemia and Iron Deficiency Anemia (IDA) Camden Study,
2000 –2004.
6-fold from 6.7% (1st trimester) to 27.3% (2nd trimester) to 45.6%
in the 3rd trimester. Only a fraction of anemic women in Camden
have iron deficiency anemia. Based on low hemoglobin for ges-
tation by CDC criteria plus low ferritin (쏝12), iron deficiency
anemia in Camden gravidas is lower—1.8% in 1st trimester, to
8.2% in 2nd trimester, and 27.4% in 3rd trimester (Figure 1).
Thus, anemia and IDA are not synonymous, even among low-
income minority women in their reproductive years.
Anemia has been called a “sickness index” for the body (4).
Apart from iron deficiency, the most frequent reason, and the
physiologic anemia of pregnancy (both discussed below) causes
include hemoglobinopathies like thalassemia, deficiencies of fo-
late/B12, and the anemia of chronic disease, which ranks second
to iron deficiency in prevalence. This anemia develops as part of
a host response to a wide range of disorders that also involve the
red cell. While anemia of chronic disease is often associated with
an underlying condition such as cancer or cardiovascular disease
or when an infectious or inflammatory process is chronic, it can
also develop when the infection or inflammation is acute. Its
diagnosis is one of exclusion (4).
PREGNANCY OUTCOME WITH MATERNAL ANEMIA
DETECTED EARLY IN PREGNANCY
Some of the increase in anemia and iron deficiency anemia
with gestation is an artifact of the normal physiologic changes of
pregnancy (5). Although the maternal red -cell mass and plasma
volume both increase during gestation, they do not do so simul-
taneously. Hemoglobin and hematocrit decline throughout the 1st
and 2nd trimesters, reach their lowest point late in the second to
early in the 3rd trimester and then rise again nearer to term (6). In
late pregnancy it is difficult to distinguish physiologic anemia
from iron deficiency anemia (5, 7). It is thus becoming clear that
the best time to detect any risk associated with maternal anemia
may be early in pregnancy.
We originally studied this issue in Camden by separating ane-
mia at entry to prenatal care and week 28 into iron deficiency
anemia and anemia from causes other than iron deficiency (5, 8).
Early in pregnancy there were clear differences in mean corpus-
cular volume (MCV) and diet in women with and without IDA
that either were not present or were greatly diminished during the
3rd trimester. At entry, women with iron deficiency anemia had
an MCV that was significantly lower (6.5 femtoliters) than other
women. During the 3rd trimester the MCV of women with IDA
was close to the mean of the other women. At entry, women with
IDA had a significantly lower energy intake (500 Kcal/d less)
than the others and, iron intake from diet was also significantly
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less (5 mg less) because of the difference in energy. During the
3rd trimester women with IDA showed little difference in the
intake of energy or of iron. At entry, both iron deficiency anemia
and anemia from other causes were associated with an increased
risks of inadequate weight gain for gestation. For women with
IDA, risk was increased 2-fold while for women with other
anemias risk was increased by about 50%. In the 3rd trimester,
IDA remained associated with a 2-fold risk of an inadequate
weight gain for gestation whereas risk was not increased for
women with other anemias. IDA at entry was associated with
greater than 2-fold increases in the risks of low birth weight
and preterm delivery, while anemia stemming from other
causes was associated with a only a small increase in risk that
was not significant. In the 3rd trimester, risk of preterm de-
livery was reduced for women with IDA and was not an
increased risk for women with other anemias (5, 8).
Scanlon and colleagues recently confirmed the relation be-
tween early anemia (based on hemoglobin alone) and preterm
delivery with retrospective data from nearly 250,000 low-
income gravidas who attended WIC clinics in eleven states (9).
Preterm delivery was increased for women with anemia during
the 1st or 2nd trimester and risk depended on the severity of the
hemoglobin deficit. For women with moderate to severe anemia
(equivalent to 95 g/L at week 12), risk was approximately dou-
bled, for women with milder anemia, risk of preterm delivery was
increased between 10%– 40%. During the 3rd trimester the asso-
ciation reversed—anemic women had a 12%–25% reduction in
the risk of preterm birth. Maternal anemia was not associated
with any increase in the risk of small for gestation births.
Data from Shanghai also suggested an effect of maternal ane-
mia on preterm delivery that was the most detectable during the
1st trimester, before maternal plasma volume expanded (10). All
gravidas were Chinese and showed little variation in parity,
smoking, or utilization of prenatal care. Rates of preterm delivery
and low birth weight, but not small for gestation births, were
increased for women who had anemia early in pregnancy. Risk of
preterm delivery and low birth weight were increased 쏜 2-fold in
moderately anemic women (90 –99 g/L) and 쏜 3-fold in those
who were severely anemic (쏝90 g/L) during the 1st trimester. At
midpregnancy and late in the 3rd trimester, the influence of ma-
ternal anemia on pregnancy outcome was markedly attenuated
but not reversed. Thus, whether or not maternal anemia increases
risk of poor pregnancy outcomes may depend on when in preg-
nancy the anemia was measured. Several studies have reported
reduced risks of preterm delivery or low birth weight or no
association between anemia and preterm birth when the relation
was studied during the 3rd trimester (11–12).
POTENTIAL MECHANISMS FOR ADVERSE
OUTCOMES
If only the women who developed iron deficiency anemia
before or early in pregnancy were at increased risk of delivering
preterm this might mean that a mechanism that involves iron
could be integral to the outcome of pregnancy. Allen (13) sug-
gested 3 potential mechanisms whereby maternal IDA might
give rise to preterm delivery: hypoxia, oxidative stress, and in-
fection. Chronic hypoxia from anemia could initiate a stress
response, followed by the release of CRH by the placenta, the
increased production of cortisol by the fetus, and an early deliv-
ery. Increased oxidative stress in iron deficient women that was
 1220S SCHOLL
not offset by endogenous or dietary antioxidants could damage
the maternal-fetal unit and result in preterm delivery. With re-
duced immune function and increased risk of infection among
iron deficient women, there would be an increased production of
cytokines, secretion of CRH, and production of prostaglandin,
increasing risk of a preterm birth.
MATERNAL ANEMIA: RANDOMIZED TRIALS OF
IRON SUPPLEMENTS
Because data on maternal anemia are from observational stud-
ies, it is not certain if the effect of anemia on pregnancy outcome
is causal and could be prevented by supplementation with iron.
Observational data on anemia imply that iron supplementation
should be started early in pregnancy, if not before, to prevent
preterm delivery. If this is true, then iron supplementation started
after midpregnancy, the usual time for most women, is unlikely
to reduce risk. A novel clinical trial was conducted in 275 preg-
nant women, all WIC participants, none anemic, who were en-
rolled at entry to care in double blind and randomized trial with
supplemental iron (30 mg/d as ferrous sulfate) or placebo until
week 28 gestation (14). All women in the trial were enrolled
before week 20, and the average gestation at entry to the study
was 10.75 앐 3.8 wk gestation. Cut-points, which rendered
women ineligible for the trial, were hemoglobin 쏝 110g/L and
serum ferritin 쏝 20 ␮g/L. At weeks 28 and 38, women who were
not anemic or iron deficient continued on either the iron or pla-
cebo arm. At those points women with serum ferritin 쏝 12 ␮g/L
received 60 mg iron/d and those with ferritin between 12 and 쏝
20 ␮g/L received 30 mg iron/d, regardless of initial assignment.
Prophylactic iron supplementation from entry to week 28 did
not increase maternal serum ferritin or hemoglobin, reduce risk
of maternal anemia, or reduce any other measures of maternal
iron status in iron supplemented women compared with controls.
However, after adjustment was made for 2 factors that differed
initially between the groups (pregravid weight and serum ferritin
concentration) the proportions with absent iron stores (ferritin 쏝
12 ␮g/L) and with IDA (Hgb 쏝 110 g/L, ferritin 쏝 12 ␮g/L) at
week 28 were significantly lower among the iron supplemented.
Supplemented women had significantly longer gestation dura-
tions (ѿ 0.6 wk), and increased infant birth weight (ѿ 206 g) than
those who were not supplemented. They also showed 4-fold
reductions in risk of infant low birth weight and preterm low birth
weight. Risk of preterm delivery was not reduced by supplemen-
tation but had been reckoned solely from the mother’s last men-
strual period (LMP) based on her recall. Failure to confirm or
modify the mother’s LMP by ultrasound would introduce an
unknown amount of error into an estimate of preterm birth.
Another cluster-randomized study with early supplementation
arrived at a similar, but not identical result. Christian et al (15)
randomized women residing in geographic sectors of rural Nepal
to one of 5 treatment arms. From early pregnancy women re-
ceived either vitamin A (1000 ␮g retinol equivalents) alone (con-
trol), vitamin A plus folic acid (400 ␮g), vitamin A plus folic acid
plus iron (30 mg). The other 2 arms had added zinc (30 mg) or
multiple micronutrients in addition to the Vitamin A. In compar-
ison to controls, gravidas receiving folate showed no reduction in
the risk of low birth weight, whereas those receiving iron plus
folate increased birth weight by 37 g and showed a reduction of
14% in risk of low birth weight.
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PREGNANCY OUTCOME WITH INCREASED IRON
STATUS AND STORES
Randomized trials of iron prophylaxis during pregnancy have
demonstrated positive effects on reducing low hemoglobin and
hematocrit, and increasing serum ferritin, serum iron and other
measures, including bone marrow iron (16 –17). A recent study
of iron containing supplement utilization from NHANES,
1988 –94 showed that 72% of pregnant and 69% of lactating
women used iron supplements during the month before they were
surveyed. However, median consumption of supplemental iron
was in excess of the tolerable upper limit of 45 mg/d in pregnant
(58 mg/d) and lactating women (57 mg/d) (18). Overall, 쏝 15%
of reproductive age women, pregnant and nonpregnant alike,
who took iron supplements, had or were being treated for anemia
within the past 3 mo. Thus, there is a potential concern that some
women who are not anemic may be taking large doses of sup-
plemental iron during pregnancy. It has been suggested that such
use may build up the mother’s iron stores and increase blood
viscosity so that utero-placental blood flow is impaired or that the
excess iron intake could cause other toxic reactions (19).
In addition to their work on anemia, Scanlon and colleagues
considered high levels of hemoglobin during the 1st and 2nd
trimesters (9). They found that high hemoglobin was associated
with an increased risk (5%–79%) of small for gestational age
(SGA) births, but not with preterm delivery. Levels that were 1
SD unit or more above the mean marked the threshold for in-
creased risk and were equivalent to 131 g/L at week 12 and 126
g/L at week 18. Likewise, Zhou et al (10) examined high hemo-
globin along with anemia. During the 1st trimester women with
hemoglobin levels exceeding 130g/L showed no increase in the
risk of SGA births but had a 쏜 2-fold increases in preterm
delivery and infant low birth weight. There were few such
women and increased risks were usually not statistically signif-
icant. Failure of hemoglobin to fall below 105 g/L was associated
with increased risk of poor outcome in a multiethnic sample of
gravidas from England (20). In the stratum of women whose
lowest hemoglobin was between 126 –135 g/L, there was a
greater than 2-fold increase in preterm delivery and low birth
weight and at the highest level, when hemoglobin remained
above 145 g/L, there was a 쏜 7-fold increase in risk of low birth
weight and 5-fold increases in risk of preterm delivery.
Hemminiki and Rimpela carried out a clinical trial of selective
versus routine iron supplementation in 2912 Finnish women
(21–23) to determine whether routine supplementation with iron
(100 mg elemental iron from at least 16 wk gestation to delivery)
in nonanemic women increased risk of high maternal hemoglo-
bin and poor fetal growth. Women randomized to the selective
group received iron supplements only when hematocrit fell be-
low 30% or hemoglobin below 100 g/L on 2 consecutive visits
after week 33. In comparison to selective supplementation, rou-
tine supplementation with iron halted the decline in hematocrit
by week 20 and did not alter infant birth weight, whereas gesta-
tion duration was increased significantly (ѿ 0.2 wk). Interest-
ingly, in both routine and nonroutine groups, a high hematocrit
was negatively correlated with birth weight and placental weight;
this correlation was first detected during the 1st trimester (23). A
recent study from the Netherlands, wherein a cohort of 240
women was monitored from before conception to delivery, un-
derscores this point. Gravidas with an early pregnancy fetal loss
had a less profound decline in hematocrit from before conception
 MATERNAL ANEMIA AND HIGH HEMOGLOBIN
to 10 wk postLMP (24). Thus, factors that underlie an adverse
pregnancy outcome (poor plasma volume expansion, increased
blood viscosity) may give rise to high maternal hemoglobin
rather than use of iron supplements.
Iron stores that are elevated for pregnancy are associated with
preterm delivery, preeclampsia and gestational diabetes mellitus.
Women with ferritin levels that are elevated for the 3rd trimester
of pregnancy (쏜41 ng/mL) have a greatly increased risk of pre-
term and very preterm delivery that has been attributed to intra-
uterine infection (25, 26). Another plausible mechanism for high
ferritin levels is failure of the maternal plasma volume to expand.
In Camden, increased IDA and lower levels of folate were found
in women who went on to have high 3rd trimester ferritin. In the
3rd trimester the situation reversed, thus implicating plasma vol-
ume expansion (26). Ferritin production also is increased with
infection and inflammation as part of the acute phase response. In
the presence of infection, macrophages produce inflammatory
cytokines that generate reactive oxygen species, releasing free
iron from ferritin (27).
IRON, MATERNAL DIABETES, AND OXIDATIVE
STRESS
Iron supplementation during pregnancy increases maternal
iron status during pregnancy including hemoglobin, serum iron,
MCV, transferrin saturation, and serum ferritin. Reactive oxygen
species are products of oxygen. When brought into contact with
a transition metal that is capable of changing valence, such as
iron, (Fe2ѿ 3 Fe3ѿ) a very reactive free radical, the hydroxl
radical is formed from oxygen via the Fenton Reaction. These
free radicals have the potential to damage cells, organs, and
tissues in the body (28). Oxidative stress over time is now thought
to be a component of the processes of aging, cancer, and the
development of cardiovascular disease. Iron overload and the
associated oxidative stress contribute to the pathogenesis and
increase risk of type 2 diabetes and other disorders. In iron over-
load, the accumulation interferes with the extraction, synthesis
and secretion of insulin (29). It is difficult for reproductive age
women to become iron overloaded because of blood loss with
menstruation. However, moderately elevated iron stores also
increase the risk of type 2 diabetes (30). Women from the Nurses
Study with high levels of ferritin (쏜107 ng/mL) were nearly 3
times more likely to develop type 2 diabetes over a 10-y interval,
independent of other risk factors such as body mass index (BMI),
age, and ethnicity. High levels of ferritin were a risk factor for the
development of gestational diabetes mellitus (GDM) in pregnant
women. Nonanemic gravidas from Hong Kong who developed
GDM during the course of pregnancy were compared with con-
trols without anemia or diabetes selected at random from the
at-risk population. Unadjusted concentrations of serum ferritin,
iron, transferrin saturation, and the post-natal hemoglobin were
significantly higher at 28 –31 wk gestation in cases with GDM
compared with controls (31).
In Camden, use of iron supplements increased serum ferritin
concentrations. At entry to care and in the 3rd trimester, gravidas
who took iron were significantly more likely to be in the highest
quintile of serum ferritin. At entry the likelihood of being in the
highest quintile was increased by 44% (OR ҃ 1.44, 95% CI
1.04 –1.99) and in the 3rd trimester it was increased 2-fold (OR ҃
2.01, 95% CI 1.48 –2.74). We were able to detect an association
between maternal serum ferritin and gestational diabetes using
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data from 쏜 1023 gravidas from Camden. Controlling for po-
tential confounding variables (age, BMI, parity, ethnicity, smok-
ing, iron supplement use), we found a 2-fold increase in risk of
GDM for women in the highest quartile of serum ferritin at entry
(AOR 2.32; 95% CI 1.06 –5.08) and nearly a 3-fold increase in
the 3rd trimester (AOR 2.9; 95% CI 1.27– 6.95) (32). This posi-
tive relation suggests that iron stores may play a role in the
development of GDM, a precursor of type 2 diabetes mellitus.
Supplementation with iron clearly augments iron status and
iron stores. Whether supplementation with iron during preg-
nancy increases oxidative stress by adding to iron stores and
creating a temporary iron surplus has been little studied. Because
an increase in oxidative stress is part of normal pregnancy, rou-
tine iron supplementation in women who were not iron depleted
or deficient might also contribute to or exacerbate oxidative
stress. Lachili et al examined the influence of an iron supplement
and vitamin C, an antioxidant that increases iron absorption, on
oxidative stress during pregnancy (33). They found that admin-
istration of an iron supplement (100 mg/d as fumarate) with
vitamin C (500 mg/d as ascorbate) during the 3rd trimester of
pregnancy increased measures of maternal iron status. An indi-
cator of oxidative stress from lipid peroxidation, plasma TBARS,
was significantly increased in the n ҃ 27 supplemented women
compared with controls (33).
We were able to confirm the presence of increased oxidative
stress in association with increased iron stores during pregnancy
(Scholl, Chen, and Stein, 2004, unpublished observations). In
Camden there is ongoing research on oxidative stress. 앒350
gravidas from the Camden cohort had urinary excretion of 8
hydroxydeoxyguanosine (8-OH-dG) measured with the Genox
kit (Genox Corporation, Baltimore). In this sample, a high level
of serum ferritin at entry (쏜59 ng/mL) was associated with a
2.7-fold (95% CI 1.40 –5.41) increased risk of having 8-OH-dG
in the highest tertile; in the 3rd trimester a similar relation was
found between high transferrin saturation (쏜21.7%) and 8
OH-dG in the highest tertile (AOR ҃ 3.3; 95% CI 1.28 – 8.11).
Thus, preliminary findings suggest an association between in-
creased iron stores and the excretion of 8-OH-dG, a marker of
oxidative damage to DNA in the maternal-fetal unit.
Risks and benefits of increased maternal iron status and stores
from prophylactic iron supplementation should be examined fur-
ther. For example, it would be important to know if higher levels
of ferritin among gestational diabetics and women who deliver
preterm represent increased iron stores as opposed to inflamma-
tion, infection, or failure of the plasma volume to expand. If
increased iron stores are implicated, then it may be appropriate to
identify an upper limit for iron-replete pregnant women beyond
which prophylactic supplementation is not indicated. While iron
supplementation may improve pregnancy outcome when the
mother is iron depleted, iron deficient or has IDA it is possible
that prophylactic supplementation may increase risk when the
mother is not. Anemia and IDA are not synonymous, even among
low-income minority women in their reproductive years.
The author has no personal or financial conflict of interest related to this
project.
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