Iron-Deficiency Anemia: Reexamining the Nature and

Magnitude of the Public Health Problem

Biological Mechanisms That Might Underlie Iron’s Effects on Fetal Growth

and Preterm Birth1,2
Lindsay H. Allen
Program in International Nutrition, Department of Nutrition, University of California, Davis, CA

ABSTRACT A negative association between anemia and duration of gestation and low birth weight has been
reported in the majority of studies, although a causal link remains to be proven. This paper explores potential
biological mechanisms that might explain how anemia, iron deficiency or both could cause low birth weight and
preterm delivery. The risk factors for preterm delivery and intrauterine growth retardation are quite similar, although
relatively little is understood about the influence of maternal nutritional status on risk of preterm delivery. Several
potential biological mechanisms were identified through which anemia or iron deficiency could affect pregnancy
outcome. Anemia (by causing hypoxia) and iron deficiency (by increasing serum norepinephrine concentrations)

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can induce maternal and fetal stress, which stimulates the synthesis of corticotropin-releasing hormone (CRH).
Elevated CRH concentrations are a major risk factor for preterm labor, pregnancy-induced hypertension and
eclampsia, and premature rupture of the membranes. CRH also increases fetal cortisol production, and cortisol
may inhibit longitudinal growth of the fetus. An alternative mechanism could be that iron deficiency increases
oxidative damage to erythrocytes and the fetoplacental unit. Iron deficiency may also increase the risk of maternal
infections, which can stimulate the production of CRH and are a major risk factor for preterm delivery. It would be
useful to explore these potential biological mechanisms in randomized, controlled iron supplementation trials in
anemic and iron-deficient pregnant women. J. Nutr. 131: 581S–589S, 2001.

KEY WORDS: ● iron deficiency ● anemia ● preterm ● low birth weight ● pregnancy
● corticotropin-releasing hormone

The article by Rasmussen (2001) in this supplement re-
views the strength and plausibility of the evidence that iron-
deficiency anemia or anemia is the cause of adverse birth
outcomes. Although there are numerous reports of an associ-
ation between maternal hemoglobin and both lower birth
weight and preterm delivery, Rasmussen concludes that evi-
dence is insufficient to prove that iron deficiency plays a causal
role in poor pregnancy outcome. To some extent, this lack of
evidence is due to the inadequate design of published studies.
The purpose of this paper is to explore the biological
mechanisms through which anemia or iron deficiency might
cause poor fetal growth and preterm delivery, regardless of
whether a causal link has been proven. Because of the complex
hormonal and physiological factors that affect pregnancy out-
come and the virtual lack of any studies of the effects of iron
deficiency on these factors, the biological mechanisms pro-
posed below are hypothetical. This article summarizes current
1
Presented at the Belmont Meeting on Iron Deficiency Anemia: Reexamining
the Nature and Magnitude of the Public Health Problem, held May 21–24, 2000 in
Belmont, MD. The proceedings of this conference are published as a supplement
to The Journal of Nutrition. Supplement guest editors were John Beard, The
Pennsylvania State University, University Park, PA and Rebecca Stoltzfus, Johns
Hopkins School of Public Health, Baltimore, MD.
2
This article was commissioned by the World Health Organization (WHO).
The views expressed are those of the author alone and do not necessarily reflect
those of WHO.
information about the biological mechanisms involved in pre-
term delivery and intrauterine growth retardation (IUGR)3
and suggests ways in which these may be affected by anemia or
iron deficiency. It is intended to provide information that will
be useful for planning which hormones and metabolites should
be measured in future studies of the role of iron deficiency and
iron-deficiency anemia in pregnancy outcome.
The review starts with a summary, based on the Rasmussen
review, of what is known about the possible effects of iron
deficiency and iron-deficiency anemia on infant size at birth
and duration of gestation. The prevalence of IUGR and pre-
term delivery is described, with a comparison of the risk factors
for these conditions. This is followed by a description of the
biological mechanisms involved in the normal delivery pro-
cess, including the central role of corticotropin-releasing hor-
mone (CRH) in determining the duration of gestation and the
association of other hormones with fetal growth. Finally,
mechanisms are proposed that might underline iron’s effects
on these processes, increasing the risk of preterm delivery and
low birth weight.
3
Abbreviations used: ACTH, adrenocorticotropic hormone; CRH, cortico-
tropin-releasing hormone; CRH-BP, CRH-binding protein; IGF, insulin-like growth
factor; IUGR, intrauterine growth retardation; LC, locus ceruleus; NE, norepineph-
rine;

0022-3166/01 $3.00 © 2001 American Society for Nutritional Sciences.

581S
582S SUPPLEMENT
Associations between iron-deficiency anemia and
pregnancy outcome
Nonintervention studies. In her review, Rasmussen sum-
marizes the results of 54 nonintervention studies that exam-
ined associations between hemoglobin or hematocrit and preg-
nancy outcome. Of these, 44 analyzed associations among
hemoglobin or hematocrit, birth weight and percentage of low
birth weight (ⱕ2500 g) deliveries. In 26 of the 44, anemia,
lower hemoglobin or hematocrit, or low ferritin concentra-
tions were significantly associated with a higher prevalence of
low birth weight, whereas in the other reports, this was not the
case. It is not known to what extent preterm delivery could
explain these observed associations between lower birth
weight and anemia because gestational age was assessed in only
10 of the 44 studies. In 5 of these 10 (2 in Papua New Guinea,
1 in India, 1 in Hong Kong and 1 in the United States),
anemia was associated with a shorter gestation period. In the
U.S. study on adolescents of low socioeconomic status, pre-
term delivery explained all of the lower birth weight associated
with iron-deficiency anemia when other potential confounders
were controlled for by regression analysis (Scholl et al. 1992).
In 21 of the 54 nonintervention studies summarized by
Rasmussen, gestation duration was not measured, and in two of
the studies, the sample was restricted to full-term births. Of the
remaining 31 studies that examined an association between
either hemoglobin or hematocrit and duration of gestation, 7
found no association, 22 found a positive association, 1 found
a negative association and 1 reported a positive association
between duration and the intake and serum concentrations of
folate. Ferritin concentrations were assessed in only six of
these reports and were positively associated with gestation
duration in four of them. We conclude that it is plausible that
the frequently observed association between maternal hemo-
globin and birth weight might be caused by a shorter gestation.
Intervention studies. Rasmussen identified 17 iron, folate,
or iron and folate intervention studies in which the effect of
the supplements on size at birth, duration of gestation or both
was assessed. The design of these studies was remarkably poor
in that false negatives (primarily from treatment of nonanemic
women), bias or potential confounders were present in nearly
all of them. Duration of gestation was assessed in only six of
the studies, and none were conducted in developing countries
or with anemic women.
Prevalence of preterm delivery and low birth weight
The most widely used definition of preterm birth is that of
the WHO, that is, birth before 37 completed weeks of gesta-
tion or ⬍295 d since d 1 of the last menstrual period. In a few
studies, preterm was defined as birth before 36 or 38 wk of
gestation.
The relative contribution of preterm delivery and fetal
growth retardation to low birth weight has been compared by
using birth weight and gestational age data from 25 developing
regions and 11 developed regions of the world (Villar and
Belizan 1982). The prevalence of low birth weight, IUGR-low
birth weight and preterm low birth weight was 23.6, 17.0 and
6.7%, respectively, for developing countries and 5.9, 2.6 and
3.3%, respectively, for developed countries. These prevalences
refer only to low-birth-weight infants and therefore underes-
timate substantially the total prevalences of intrauterine
growth restriction and preterm delivery. In addition, especially
in developing countries, preterm delivery is often not diag-
nosed at all or is diagnosed inaccurately.
Preterm delivery is the main cause of perinatal mortality
and morbidity in industrialized countries, in which the prev-
alence has not fallen in the last few decades. In fact, in a large,
carefully conducted Canadian study, the rate of preterm births
over the past 20 years increased from 6.6 to 9.8% for ⬍37 wk,
1.7 to 2.3% for ⬍34 wk and 1.0 to 1.2% for ⬍32 wk (Kramer
et al. 1998). Although half of the apparent increase in prev-
alence was due to earlier use of ultrasound dating, other factors
such as preterm induction of labor, use of cocaine and an
increase in the number of pregnant unmarried women have
tended to increase the prevalence.
Risk factors for low birth weight and preterm delivery:
similarities and differences
Nonnutritional causes of fetal growth retardation include
hemorrhage, multiple births, uterine and placental abnormal-
ities, parental size and genetics, and major congenital malfor-
mations. These explain up to 50% of the variance in birth
weight in both developed and developing countries (Villar and
Belizan 1982). In developing countries, more IUGR is due to
low maternal weight and height (undernutrition during the
mother’s development), low pregnancy weight gain (which is
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influenced by energy intake during pregnancy) and maternal
infection. Low maternal weight at conception and low weight
gain during pregnancy are independent predictors of poor fetal
growth and IUGR. Low maternal height also plays a role
independently of low body mass index.
In a large sample of Canadian women with gestational time
confirmed by ultrasound, significant predictors of preterm birth
(before 37 wk) included low maternal stature, noncompletion
of high school, unmarried status, smoking, diabetes, urinary
tract infection within 2 wk of delivery, prepregnancy hyper-
tension, severe pregnancy-induced hypertension, previous his-
tory of a preterm birth, low birth weight or infant death at
birth (Kramer et al. 1992). Anemia was not mentioned in the
analysis.
The statement was made that “the degree of overlap be-
tween the sets of risk factors for preterm delivery and growth
retardation (IUGR) is so great that it is easiest to list the
discrepancies” (Yu and Wood 1987). Of the many risk factors
for preterm delivery, a few (including cervical trauma, dieth-
ylstilbestrol exposure, maternal infections and febrile states)
are associated with preterm delivery, but not with IUGR
(Bakketeig 1991, Institute of Medicine et al. 1985). The
relative risks of preterm delivery and IUGR for each risk factor
are usually different, however.
The relationship between maternal nutrition and risk of
preterm delivery has not been studied adequately. Most inves-
tigators reported no relationship between maternal nutritional
status or interventions and duration of gestation. However, as
observed by Kramer et al. (1992), most studies had major
design problems, including the following: assessment of total
pregnancy gain, which is affected by duration, rather than rate
of gain or net gain; use of average rate of gain, which is also
affected by length of gestation because rate is slower in the last
trimester; the confounding effect of fetal size later in gestation;
the inclusion of induced deliveries; and poor assessment of
gestational age. Reported date of last menstrual period is prone
to significant error especially at the extremes of gestational
age. The use of ultrasound rather than reported date of the last
menstrual period lowers the estimated prevalence of small for
gestational age by ⬃30 –50% in industrialized countries
(Bakketeig 1991).
Maternal stress, anxiety and other psychological factors
appear to be more strongly associated with risk of preterm
delivery rather than with risk of IUGR (Hedegaard et al. 1996,
 IRON-DEFICIENCY ANEMIA AND PRETERM DELIVERY
Lobel et al. 1992, Nordentoft et al. 1996). One of the more
certain risk factors for preterm delivery, maternal infection,
has been implicated in up to 40% of cases (Kurki et al. 1992).
Thus, there is substantial overlap between the risk factors
for preterm delivery and IUGR. Moreover, as will be discussed
below, there are strong links in the underlying biological
mechanisms associated with these two outcomes.
Biological mechanisms involved in the normal delivery
process
Our understanding of the biological mechanisms that con-
trol the timing of delivery is relatively recent, with major
advances occurring in the mid-1990s (Smith 1998). As a
result, there is relatively little information on factors that
affect these mechanisms and virtually none on nutritional
factors. To some extent, the lack of information is due to the
ethical difficulties of doing intervention trials that could in-
fluence delivery in humans. Animal models have been useful,
and the basic mechanism underlying parturition in sheep had
been identified by the mid-1980s. However, the ovine mech-
anisms and those in some primates are different from those in
humans.
Early in pregnancy, the hormone progesterone, secreted by
the placenta, keeps the smooth muscle cells of the uterus
relaxed and the cervix tightly closed as a result of its influence
on the relatively inflexible collagen fibers. Later in pregnancy,
the secretion of estrogen by the placenta increases dramati-
cally and parturition begins when the influence of estrogen is
greater than that of progesterone.
The importance of corticotropin-releasing hormone
To a great extent the process of delivery is regulated by
CRH, which is produced in the maternal and fetal compart-
ments of the placenta. CRH mRNA has been detected in
placental trophoblast cells at 8 wk of gestation and does not
appear until the placental syncitioblasts are formed (Riley et
al. 1991). Although increases in plasma concentrations are
seen in some women as early as the second trimester (Goland
et al. 1986), in most women, levels are low until the third
trimester and then rise rapidly (Emanuel et al. 1994, Goland et
al. 1986). The mRNA for placental CRH and the release of
the hormone into maternal plasma increase as much as 50-fold
during the third trimester. CRH concentrations in maternal
plasma vary up to 50-fold in late pregnancy.
The CRH produced by the placenta is secreted into the
fetal circulation in amounts high enough to stimulate the
production of adrenocorticotropic hormone (ACTH, cortico-
tropin) by the anterior pituitary of the fetus. This may occur
through the binding of CRH with fetal adrenal CRH recep-
tors. Some CRH secreted by the fetal hypothalamus may also
stimulate fetal ACTH production. The result is an increased
production of cortisol by the fetal adrenal. Fetal cortisol blocks
the inhibitory effect of progesterone on placental CRH pro-
duction. Earlier in pregnancy, the high levels of progesterone
acted as a brake on the secretion of placental CRH and fetal
cortisol by competing with cortisol for the glucocorticoid
receptors (Karalis et al. 1996, Majzoub and Karalis 1999). As
cortisol concentrations rise, the hormone binds to these pla-
cental glucorticoid receptors, for which it has a 2– 4 times
greater affinity than does progesterone (Ojasoo et al. 1988).
This positive feedback loop causes additional production of
placental CRH and fetal cortisol.
The increasing concentrations of placental CRH and of
ACTH from the fetal pituitary stimulate the fetal adrenal to
583S
produce dehydroepiandrosterone sulfate, which is converted to
estrogen by the placenta. Changes occur as a result of the
increase in estrogen concentrations. The cells of the myome-
trium synthesize connexin molecules, which move to the cell
membrane and connect the cells electrically so that they will
contract synchronously during labor; muscle cells in the uterus
produce large numbers of oxytocin receptors, necessary for this
hormone to cause contraction of the cells during labor; in
addition, the synthesis of prostaglandins by placental tissues
overlying the cervix is increased, which induces the produc-
tion of enzymes in the cervix that digest collagen and make
the cervix flexible during delivery of the fetus.
Despite the high concentrations of CRH in maternal
plasma, maternal plasma concentrations of ACTH and corti-
sol remain relatively normal during pregnancy. This is proba-
bly due to CRH-binding protein (CRH-BP), which neutralizes
CRH earlier in pregnancy. The mRNA for CRH-BP is ex-
pressed in the placenta, decidua, myometrium and fetal mem-
branes during pregnancy and reduces the amount of active
CRH in the maternal circulation (Linton et al. 1988). How-
ever, during the third trimester, the concentration of CRH-BP
declines to about one third the peak concentration, falling by
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about 60% during wk 34 and 35 (Chrousos 1999). This results
in an increased amount of free CRH and explains the substan-
tial increase in CRH and cortisol in late pregnancy. CRH and
CRH-BP form a dimer complex that may interact with recep-
tors to produce the final biological effect (Behan et al. 1993).
CHR-BP has also been shown to reduce the CRH-induced
contractile activity of myometrial strips (Petraglia et al. 1995).
The binding of CRH to CRH-BP likely also causes the com-
plex to be cleared from the circulation, explaining the fall in
CRH-BP concentrations in late pregnancy (Woods et al.
1994).
The role of CRH in preterm labor. The cause of preterm
labor can be physiological, in which a factor required for
normal initiation of labor appears too early in gestation, or
pathological, in which the initiating factor is abnormal but
may induce the normal physiologic mechanisms.
Physiological preterm labor. Abnormal maternal CRH con-
centrations are highly associated with risk of preterm or post-
term labor, as would be expected from the preceding discus-
sion. More than 10 years ago, women in preterm labor were
reported to have high plasma concentrations of CRH com-
pared with control women at the same stage of gestation
(Wolfe et al. 1988). Subsequently, a large prospective cohort
study showed that women who had an abnormally high CRH
concentration early in pregnancy were highly likely to have a
preterm delivery (McLean et al. 1995). In fact, higher risk of
either pre- or post-term delivery could be predicted even at
16 –20 wk of gestation on the basis of higher or lower concen-
trations of CRH in maternal serum, respectively. Regardless of
the final concentrations, CRH concentrations increase expo-
nentially during pregnancy. This sequence of events has been
likened to a biological clock in the fetoplacental unit and
determines the duration of pregnancy from an early stage
(Smith 1999). Higher concentrations of CRH during labor
also predict a shorter labor duration (McLean et al. 1995).
Pathological causes of preterm labor. Documented causes of
increased placental CRH secretion in humans include hyp-
oxia, inflammatory cytokines, glucocorticoids, stress (includ-
ing noninflammatory and inflammatory stress), preeclampsia
and eclampsia.
Concentrations of CRH in maternal plasma were measured
in one study of abnormal pregnancies (Wolfe et al. 1988).
Levels were not elevated in maternal diabetes but were signif-
icantly higher in pregnancies with antepartum hemorrhage at
584S SUPPLEMENT
28 wk (but not later), during the third trimester of twin
pregnancies, and in women with pregnancy-induced hyperten-
sion, premature rupture of the membranes or preterm labor
(with higher concentrations from at least as early as 28 wk). In
some of the pregnancies, CRH concentrations were elevated
11 wk before any other symptoms appeared.
Normal CRH concentrations do not completely guarantee
a normal delivery date because fetal infections and other
problems can cause early delivery regardless of CRH, and there
is considerable interindividual variability in normal concen-
trations. However, abnormal CRH concentrations are highly
predictive of the duration of gestation.
Other actions of CRH. As will be explained in more
detail below, CRH plays a major role in both the maternal and
fetal stress systems. It has been estimated that during a stressful
event, the amount of CRH released is so high and the avail-
able time for exposure to CRH-BP is so low that maternal
CRH will not be completely quenched by CRH-BP. This
means that CRH can still act as a stress hormone during
pregnancy (Linton et al. 1990). Additional actions of CRH
include the following: stimulation of prostaglandin F2␣ and
prostaglandin E2 production by fetal membranes; potentiation
of the action of oxytocin and PGF2␣, which are uterotonics;
and activation of CRH receptors on the smooth muscle of the
myometrium. CRH and oxytocin interact synergistically in the
presence of prostaglandins to cause myometrial contractility.
Elevated CRH concentrations also predicted a significantly
lower fetal heart rate reactivity in response to vibroacoustic
stimuli at 31–32 wk of gestation independently of the length
of gestation (Sandman et al. 1999).
CRH in other species. An understanding of the differ-
ences in CRH metabolism across species is important for the
appropriate interpretation of the literature on experimental
animals. In sheep, CRH is secreted from the hypothalamus of
the fetal brain rather than by the placenta. The CRH induces
the fetal pituitary to secrete ACTH and subsequently the fetal
adrenal to produce cortisol, as in humans. However, there is
no ovine CRH-BP. In primates, as in humans, most of the
CRH comes from the placenta rather than the fetal brain, but
CRH induces placental estrogen secretion through a different
pathway. CRH increases exponentially in the plasma of chim-
panzees in the last half of gestation as in humans, but concen-
trations fall during this time in other primates, including
baboons.
Hormones that influence fetal growth
The clinical pattern of poor fetal growth depends on the
cause of the poor growth, its timing and its duration. Earlier
undernutrition tends to cause symmetric growth retardation,
whereas later undernutrition causes the proportions of the
fetus to be more asymmetric. Many factors have been associ-
ated with increased risk of fetal growth retardation, as re-
viewed elsewhere (Lin and Santolaya-Forgas 1998).
The insulin-like growth factor (IGF) system is probably the
most important with respect to fetal growth, and IGF-1 is the
most important hormone (Gluckman and Harding 1997). Fe-
tal IGF-1 is secreted in response to fetal glucose concentra-
tions (Oliver et al. 1993). IGF directs nutrients to insulin-
sensitive tissues, promoting glycogen and fat storage in muscle,
liver and adipose tissue. Substrate availability is the main
determinant of fetal IGF-1 levels (Gluckman et al. 1983). In
animal models, maternal starvation quickly lowers fetal IGF-1
concentrations and subsequently fetal growth (Bassett et al.
1990). Maternal IGF-1, IGF-2 and insulin do not cross the
placenta but they may affect placental function; maternal
plasma IGF-1 in rodents also correlates with fetal growth
(Mirlesse et al. 1993). Most newborn IUGR infants have low
levels of IGF-1. In a comparison of 15 normal newborns and
30 with IUGR, the IUGR group had significantly lower con-
centrations of IGF-1 and higher concentrations of IGF-bind-
ing protein-3 (Cianfarani et al. 1998). In a case-control study
of 76 full-term deliveries, of which 31 were IUGR, cord blood
concentrations of IGF-1, insulin and thyroid-stimulating hor-
mone were lower in the IUGR group, but higher concentra-
tions of growth hormone were present (Nieto-Dı́az et al.
1996).
Cortisol inhibits longitudinal growth of the sheep fetus in
late gestation (Fowden et al. 1996) and probably plays a major
role in regulating growth at this time. In sheep, preventing the
cortisol surge by fetal adrenalectomy abolished the normal
slowing of growth at term, and infusing cortisol earlier in
gestation lowered the rate of longitudinal growth to that
normally seen in late pregnancy (Fowden et al. 1996). Over
the entire gestation period, mean plasma cortisol concentra-
tions accounted for 40 –50% of the variation in fetal crown-
rump length increment. Cortisol suppresses the production of
IGF-2 in fetal sheep (Li et al. 1993). It also appears to switch
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fetal cells from proliferation to differentiation.
Fetal insulin production is also important for normal pro-
tein synthesis in the fetus. IUGR fetuses have small Islets of
Langerhans and lower insulin concentrations. Some members
of the growth hormone–prolactin gene family are produced
only by the placenta. These include placental growth hor-
mone, placental lactogens and prolactin-related proteins. A
placental growth hormone appears in maternal circulation by
early in the second trimester and its concentration rises until
delivery. Plasma from the mothers of IUGR infants have
reportedly lower concentrations of this hormone (Mirlesse et
al. 1993), although the hormone does not appear in fetal
circulation. Human placental lactogen is detectable in mater-
nal circulation by ⬃6 wk of pregnancy and increases up to
term. It stimulates nitrogen retention and insulin secretion
and is lipolytic. Although it might maintain fetal glucose
during maternal starvation, its importance for fetal growth is
not clear. However, human placental lactogen may stimulate
IGF production by the fetus (Schocknecht et al. 1992).
Mechanisms that might underlie iron’s effects on preterm
delivery and fetal growth
There have been no studies of the effect of iron deficiency
or anemia on the biological mechanisms that can affect pre-
term delivery or fetal growth. In fact, only one study was found
in which any hormonal differences were examined in relation
to maternal iron status and hemoglobin concentrations in
pregnancy. In population studies, placental size is inversely
related to hemoglobin concentration across a wide range of
hemoglobin values (Godfrey et al. 1991). By 18 wk of preg-
nancy, placental volume may already be inversely correlated
with maternal hemoglobin and serum ferritin concentrations,
even in industrialized countries. On the basis of this observa-
tion, associations between maternal hemoglobin and iron sta-
tus and factors known to affect placental size, i.e., human
chorionic gonadotropin and human placental lactogen, were
assessed during the first trimester of pregnancy in 175 women
who were consulting about pregnancy termination. The aver-
age duration of gestation was 68 d. Maternal hemoglobin was
significantly negatively correlated with the levels of human
chorionic gonadotropin and human placental lactogen across
the normal hemoglobin range. Although serum ferritin con-
centrations were low in 21% of the women, there was no
 IRON-DEFICIENCY ANEMIA AND PRETERM DELIVERY
correlation with the hormone concentrations. The authors
suggest that the oxygen content of maternal blood may have
had an important influence on the development of the pla-
centa and subsequently on human chorionic gonadotropin and
human placental lactogen concentrations. There is no reason
to believe that increased human chorionic gonadotropin or
human placental lactogen concentration would have an ad-
verse effect on pregnancy outcome.
Because virtually nothing is known about the effects of iron
deficiency or anemia on the biological mechanisms that reg-
ulate the duration of gestation and fetal growth, the discussion
in this section focuses mainly on other factors and illnesses
that are known to influence these mechanisms and that could
plausibly explain any effects of anemia or iron deficiency. The
postulated biological mechanisms are as follows.
Iron deficiency or anemia may increase the stress hor-
mones, norepinephrine and cortisol. Iron deficiency in-
creases norepinephrine (NE) concentrations (Dallman 1986),
as does hypoxia (Gülmezoglu et al. 1996). Norepinephrine is a
strong stimulus for the release of CRH (Calogero et al. 1988)
and cortisol. The CRH and locus ceruleus/NE (LC/NE) sym-
pathetic systems respond similarly to many of the same neu-
rochemicals (Chrousos and Gold 1992). Iron deficiency and
anemia were not mentioned among these, but this has not
been studied. Norepinephrine infusion into pregnant sheep
caused a reduction in fetal protein synthesis and accretion,
indicating adverse effects on fetal growth (Milley 1997).
There is virtually no information concerning the effect of
iron deficiency or anemia on cortisol secretion. In one rat
study of the effect of an iron-free diet, the iron deficiency
caused stress, as evidenced by a higher serum cortisol concen-
tration (Campos et al. 1998).
Chronic hypoxia activates the stress response. Low he-
moglobin concentrations can cause a state of chronic hypoxia,
which is presumably exacerbated in pregnancy when oxygen
demands are particularly high because of the metabolism of the
mother and the fetus. Although changes in transplacental
oxygen transfer are relatively small when maternal hemoglo-
bin concentrations fall, oxygen transfer to the fetus is probably
reduced in anemic women (Viteri 1994). Infant birth weight
was directly related to calculated maternal arterial oxygen
content in a study of women living at high altitude in the
United States (Moore et al. 1982b). Moreover, either mater-
nal or fetal hypoxia could activate the stress response, de-
scribed below.
Although there is no information on the effect of low
hemoglobin concentrations, some information is available
concerning the effects of other situations in which chronic
hypoxia affects pregnancy outcome. These include animal
models in which hypoxia is caused by reducing blood flow,
using a hypobaric chamber, high altitude, smoking and hemo-
globinopathies. Fetal hypoxia can also be caused by factors
that reduce maternal uteroplacental circulation. For example,
preeclampsia with chronic hypertension produces a low partial
pressure of oxygen in the fetus as well as reduced glucose and
fetal glycogen stores.
Hypoxia-induced stress responses. Stress may be defined as
“a state of threatened homeostasis, which is reestablished by a
complex repertoire of physiologic and behavioral adaptive
responses of the organism” (Chrousos 1998). CRH plays a
major role in the response to stress as well as being a major
player in fetal development and delivery, and although it has
never been tested directly, it is plausible that iron deficiency
creates a stress response. As stated by Chrousos (1998), “the
systems responsible for reproduction, growth and immunity are
585S
directly linked to the stress system, and each is profoundly
influenced by the effectors of the stress response.”
In the nonpregnant individual, the stress system is located
in both the central nervous system and the periphery. Its role
is to create physiological changes that redirect energy, oxygen
and nutrients to the central nervous system and stressed body
sites, and behavioral changes such as fight-or-flight responses.
The stress system is complex; its description is beyond the
scope of this review. More detailed reviews are available
(Chrousos 1998, Chrousos et al. 1992, Stratakis et al. 1995).
Systems of relevance here include the following: the CRH
system, which is found throughout the brain (particularly in
the hypothalamus and the medulla) and works synergistically
with arginine-vasopressin neurons of the hypothalamus; the
LC/NE system in the medulla and pons of the brain, and their
peripheral effectors including the hypothalamic-pituitary-ad-
renal axis; the efferent sympathetic/adrenomedullary system;
and components of the parasympathetic system, which coor-
dinate the stress response.
CRH is the primary regulator of the hypothalamic-pitu-
itary-adrenal axis, and administration of CRH can produce
most of the physiological and behavioral responses to stress,
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including stimulation of ACTH production by the pituitary
and glucocorticoid production by the adrenals. The LC/NE
system produces epinephrine and norepinephrine. There are
numerous interactions among the components of the stress
system, including a positive feedback loop between the CRH
and LC-NE/sympathetic systems so that activation of one
system causes activation of the other. As discussed above, iron
deficiency causes an increased production of norepinephrine,
and norepinephrine is a strong stimulus of CRH secretion
(Calogero et al. 1988).
The fetal hypothalamic-pituitary-adrenal axis is highly re-
sponsive to stress, which leads to the increased release of
glucocorticoids as a central adaptive mechanism. The glu-
cocorticoids cause the catabolism of fat, glycogen and protein,
with a subsequent increase in blood glucose concentrations.
Over time, chronically elevated glucocorticoid concentrations
can, however, lead to impaired tissue growth and muscle
atrophy.
The stress system is closely integrated with other parts of
the central nervous system that regulate reproduction, growth
and immunity, as well as behavior and emotion.
Hypoxia induces maternal and fetal stress, and the release of
CRH. “Hypoxia stimulates CRH production in cultured (pla-
cental) cells . . . which may be associated with the increased
concentration of CRH found in the blood of women with
toxemia of pregnancy and in the umbilical circulation of
subjects with IUGR and reduced umbilical artery blood flow.”
This statement was made in a review by Smith (1998), a
pioneer in CRH research; unfortunately, no references to the
research supporting this statement were included.
Creating a chronic or acute hypoxic state is the classical
way in which to study the effects of stress in pregnant animal
models. Hypoxia is induced in various ways, including partial
ligation of the uterine arteries, hypobaric chambers and partial
occlusion of the umbilical artery. In pregnant sheep, acute
short-term hypoxia (hours to 2 wk) causes an increase in
ACTH and cortisol within ⬃3 h. Concentrations stay ele-
vated for at least 7 h, falling to normal after 16 h (Challis et
al. 1986).
When reduced uterine blood flow was used to lower the
fetal arterial oxygen saturation in sheep (Hooper et al. 1990),
there was a seven- to eightfold increase in fetal plasma epi-
nephrine after 2 h that normalized by 12 h. Fetal NE, cortisol
and prostaglandin E2 were increased three- to fourfold after 2 h
586S SUPPLEMENT
and remained higher during at least the next 12 h (Ducsay
1998). Before 126 d of gestation in a similar hypoxic sheep
model (the normal duration of gestation in the sheep is ⬃150
d), there was no significant effect of hypoxia on fetal plasma
noradrenaline concentrations, but after this, concentrations
increased more than sixfold compared with controls, and
adrenaline increased fourfold (Coulter et al. 1990). In a sheep
model, fetal hypoxia also reduced the transport of amino acids
to the fetus (Milley 1988).
Stress is associated with IUGR. CRH is released from the
hypothalamus in all individuals in response to stress in addi-
tion to being produced by the placenta during pregnancy.
During pregnancy, the normal stress signal may be amplified by
the placental release of CRH. Placental CRH and hypotha-
lamic CRH are similar in structure. Plasma concentrations are
nondetectable in nonpregnant adults.
Is placental CRH also stimulated by chronic fetal stress? To
investigate this question, CRH was measured in the cord blood
of IUGR (at 26 – 40 wk) and normal infants matched by
gestational age (Goland et al. 1986). The mean umbilical cord
plasma CRH concentration was 206 ⫾ 26 pmol/L in the
IUGR infants and 49 ⫾ 17 pmol/L in the appropriate-for-
gestational-age infants, a significant difference. Similarly,
mean plasma ACTH was significantly higher in the IUGR
samples (5.7 ⫾ 1.2 vs. 3.3 ⫾ 0.7 pmol/L). Mean cortisol
concentrations did not differ, but the mean dehydroepiandro-
sterone sulfate level was significantly lower in the IUGR group
(4.8 ⫾ 0.6 vs. 7.7 ⫾ 0.6 ␮mol/L). CRH concentrations were
significantly correlated with both ACTH and cortisol concen-
trations and negatively correlated with dehydroepiandros-
terone sulfate levels. Although cesarean section and maternal
hypertension both increased CRH in the IUGR group (but not
the appropriate-for-gestational-age group), concentrations
were still elevated (to a mean of 131 ␮mol/L) in the IUGR
infants delivered vaginally. The authors concluded that
chronic stress stimulated CRH production by the placenta and
may have affected fetal pituitary-adrenal function in these
high risk pregnancies. The nature of this stress was not iden-
tified, and it is not clear whether it originated from the mother
or the fetus. The negative association between CRH and fetal
androgen secretion was reported in other studies in which
there was intrauterine stress, such as pregnancy hypertension
(Parker et al. 1986).
In a comparison of IUGR and appropriate-for-gestational-
age infants in Italy, a strong inverse correlation (r ⫽ ⫺0.54, n
⫽ 30) was observed between length gain in the first 3 mo of
life and cortisol concentrations at birth. In the appropriate-
for-gestational age group, cortisol was inversely correlated with
IGF-1 (n ⫽ 15, r ⫽ ⫺0.75, P ⬍ 0.002) and positively associ-
ated with IGF binding protein-1 (r ⫽ 0.52, P ⬍ 0.05) but no
associations between cortisol and IGF-factors were seen in the
IUGR group (Cianfarani et al. 1998).
Maternal stress is associated with preterm delivery. In a test of
the general hypothesis that maternal stress is associated with
elevated maternal plasma concentrations of CRH and a sub-
sequently higher risk of preterm birth, Hobel et al. (1999b)
measured CRH at 18 –20, 28 –30 and 35–36 wk in 524 ethni-
cally and socioeconomically diverse pregnant women from
California. Of this group, 18 women had spontaneous onset of
preterm labor. Their samples were compared with those of 18
control women who delivered at term, matched by age, pre-
vious birth outcome, smoking status and race. The preterm
delivery cases had significantly higher plasma CRH and adre-
nocorticotropic hormone at all three gestational periods and
higher cortisol concentrations at 18 –20 and 28 –30 wk. Ma-
ternal stress level at 18 –20 wk, assessed by interview, predicted
a significant amount of variance in CRH at 28 –30 wk gesta-
tion, with CRH at 18 –20 wk controlled for. The authors
concluded that maternal stress and CRH concentrations may
be good markers for risk of preterm birth.
In a prospective study of 8719 Danish women with single-
ton pregnancies, those who reported one or more highly stress-
ful life events had a 1.76 times greater risk of preterm delivery
than those without stressful events (Hedegaard et al. 1996).
The association was strongest for events occurring between 16
and 30 wk. Sandman et al. (1997) found that higher maternal
stress at 28 –30 wk of gestation was a significant predictor of
both gestational age at birth and birth weight. Maternal stress
in the third trimester was associated with higher levels of
maternal ACTH and cortisol.
Pregnancy outcome in other hypoxic situations. Pregnant
women who are used to living at high altitude have a substan-
tially higher incidence of IUGR but not of preterm deliveries
(McCullough and Reeves 1977, Moore et al. 1982b, Sabrevilla
et al. 1968). The same is true in sheep kept in conditions of
chronic high altitude hypoxia (Ducsay 1998). The higher risk
of IUGR occurs even though there are maternal and fetal
adaptations to high altitude, including maternal hyperventi-
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lation and increased hemoglobin concentrations (Moore et al.
1982a). At high altitude, placentas have more fetal capillaries
at the periphery of the villi, larger intervillous spaces, a re-
duced volume of villi, and in some studies, an increase in
placental size (Jackson et al. 1988). In anemia, there is also an
inverse correlation between maternal hemoglobin concentra-
tion with placental volume that is evident by at least 18 wk of
gestation (Godfrey et al. 1991).
Not all infants born at high altitude are small. At an
elevation over 3000 m in the United Statues, three maternal
characteristics were identified as related to birth weight: hy-
poventilation, no increase in ventilation and arterial oxygen
saturation from early to late gestation and a falling hemoglobin
concentration during pregnancy that leads to a lower arterial
oxygen content in the last trimester (Moore et al. 1982a). This
study illustrates the limited adaptability to lower maternal
arterial oxygen concentration and suggests a strong influence
of the oxygen concentration on birth weight.
The partial pressure of oxygen is lower in the blood of
smokers. In women who smoke, the placenta is smaller and
there is a reduction in the capillary volume of the villi, as well
as other adverse changes (Jauniaux and Burton 1992). Smok-
ing is the most important predictor of IUGR in developing
countries (Kramer 1998), where it explains much of the dis-
parity in IUGR prevalence among women of lower and upper
socioeconomic status.
In preeclampsia with hypertension, the partial pressure of
oxygen in maternal and fetal blood is low. Women with
preeclampsia have higher concentrations of CRH and lower
concentrations of CRH-BP (Perkins et al. 1995). CRH con-
centrations are elevated before the development of preeclamp-
sia. In a relatively small sample, 18 patients with spontaneous
preterm delivery and 23 patients who developed pregnancy
hypertension were matched to women who delivered at term.
The preterm delivery cases had significantly higher concen-
trations of CRH and significantly lower CRH-BP–CRH dimer
complex concentrations at 18 –20, 28 –30 and 35–36 wk of
gestation. The hypertension cases also had elevated CRH as
early as 18 –20 wk (but not as high as the preterm delivery
cases) and low CRH-BP (but not as low as the preterm cases)
(Hobel et al. 1999a).
Iron-deficiency anemia may increase oxidative stress.
The fetoplacental unit is very susceptible to oxidative damage
induced by reactive oxygen species. Oxidative stress is one
 IRON-DEFICIENCY ANEMIA AND PRETERM DELIVERY
mechanism thought to cause preeclampsia, pregnancy-induced
hypertension and pregnancy-induced diabetes (Cester et al.
1994, Poranen et al. 1996). Interest is increasing in the pos-
sibility that antioxidant nutrients might improve pregnancy
outcome by reducing oxidative stress (Scholl and Stein 2000,
West et al. 2000).
The lipids of the brush border membrane of the placental
syncitioblast are susceptible to peroxidation by being in con-
tact with oxidants in the maternal blood. Scavengers of highly
reactive oxygen species, including antioxidant enzymes such as
superoxide dismutase, catalase and glutathione reductase, pro-
tect against peroxidation. These enzymes inhibit lipid peroxi-
dation. Placental oxidant-antioxidant imbalance might cause
release of products of lipid peroxidation into the fetal circula-
tion with subsequent damage to endothelial cell membranes.
Iron deficiency may cause increased oxidative stress because
it causes erythrocytes to be more susceptible to oxidative
damage. Erythrocytes are normally protected from oxidative
stress caused by free radicals released from the potentially
dangerous combination of iron and oxygen. Mechanisms that
achieve this protection include superoxide dismutase, reduced
glutathione and catalase. However, microcytic erythrocytes
have a shorter survival time partly because of oxidative dam-
age to the erythrocyte membrane (Diez-Ewald and Layrisse
1968, Vetore and Tedesco 1975). In addition, in ␤-thalasse-
mia, for example, excess globin chains (due to low hemoglo-
bin) autoxidize and release heme and produce superoxide eight
times faster than does normal hemoglobin. In a comparison of
control subjects with those with iron-deficiency anemia and
␤-thalassemia trait, the group with iron-deficiency anemia had
significantly higher malondialdehyde (by ⬃50%) and super-
oxide dismutase (by 40%) concentrations per unit hemoglo-
bin. Also, concentrations of erythrocyte pyrimidine 5⬘-nucle-
otidase, the enzyme most sensitive to sulfhydryl group damage
in vivo, are lower in iron-deficiency anemia (Vives Corrons et
al. 1995). In 26 Israeli patients with iron-deficiency anemia
compared with 10 healthy control subjects, erythrocytes had
higher levels of reduced glutathione and normal malondialde-
hyde concentrations (Bartal et al. 1993). Iron-deficient cells
were more sensitive than control cells to high concentrations
of peroxides.
When the effect of iron deficiency on lipid peroxidation
and antioxidant enzyme activity was examined in rats, the
iron-deficient group had significantly lower liver production of
malondialdehyde and activity of superoxide dismutase and
higher catalase activity (Rao and Jagadeesan 1996). When
treated with a carcinogen (dimethyl hydrazine, which pro-
duces active oxygen species), unlike controls, the iron-defi-
cient rats did not respond with an increase in glutathione
peroxidase activity. Similarly, superoxide dismutase activity
fell much more in the iron-deficient group than in iron-replete
controls when treated with the carcinogen. The investigators
speculated that the iron-sufficient rats were better able to
eliminate oxygen radicals, whereas iron deficiency increased
susceptibility to oxidative stress.
Iron deficiency may increase the risk of maternal infec-
tions. There is some evidence that iron deficiency adversely
affects immune function. For example, it can alter the prolif-
eration of T and B cells, reduce the killing activity of phago-
cytes and neutrophils, and lower bactericidal and natural killer
cell activity.
Infection is one of the main pathological risk factors for
preterm labor. The presence of bacteria or inflammatory cyto-
kines in amniotic fluid or chorioamnionitic membranes is
strongly associated with preterm labor and premature rupture
of the membranes. The bacteria are believed to come from the
587S
vagina. Early bacterial vaginosis (before 16 wk) is associated
with a relative risk of preterm delivery of 5–7.5. If this con-
dition occurs after 26 wk, the risk is 1.4 –1.9 (Kurki et al.
1992). There is potential for CRH to regulate inflammatory
responses and vice versa. The cytokine interleukin-1 stimu-
lates production of CRH, and CRH in turn regulates cytokine
production by immune effector cells. Because maternal stress is
associated with preterm birth, abnormalities in the regulation
of CRH and the production of inflammatory cytokines may be
a mechanism that could form the pathophysiological basis for
this association.
Falkenberg et al. (1999) examined the effect of maternal
infections on the fetal hypothalamic-pituitary-adrenal axis.
Subjects were 361 women with normal pregnancy (including
some with preterm delivery) and 110 with infections. Cord
blood was analyzed at delivery, which occurred between 24
and 44 wk of gestation. The infants born to women with
infections were born 1.5 wk earlier, and cord blood concen-
trations of cortisol and dehydroepiandrosterone sulfate were
significantly higher. The authors suggested that products of the
activated immune system of mothers with infections may have
crossed the placenta and activated the fetal hypothalamic-
Downloaded from jn.nutrition.org by guest on March 4, 2015
pituitary-adrenal axis.
Cortisol has been reported to inhibit the activity of natural
killer cells both in vitro and in vivo. In a study of the effect of
delivery method on cortisol in cord blood, natural killer cell
activity in the cord blood of the group with the low cortisol
concentrations (because of cesarean delivery and general an-
esthesia) was twice that of the two groups with higher cortisol
concentrations (De Amici et al. 1999).
Implications for future studies
Future studies of either associations between maternal iron
status and pregnancy outcome or of the effect of iron supple-
ments on pregnancy outcome should evaluate changes in the
biological mechanisms that affect preterm delivery and fetal
growth. This review has identified several likely candidates,
including CRH and cortisol, IGF-1, indicators of oxidative
stress and immune function. These biological factors are likely
to be much more sensitive to changes in maternal iron status
than are gross outcome measures such as birth weight and
length of gestation. They also support the plausibility of a
functional role for iron status in pregnancy outcome and may
help to identify risk factors for poor pregnancy outcome as well
as effective intervention strategies.
LITERATURE CITED
Bakketeig, L. (1991) Ultrasound dating of pregnancies changes dramatically
the observed rates of pre-term, post-term, and small-for-gestational-term.
Iatrogenics 1: 174 –175.
Bartal, M., Mazor, D., Dvilansky A. & Meyerstein, N. (1993) Iron deficiency
anemia: recovery from in vitro oxidative stress [see comments]. Acta Haema-
tol. 90: 94 –98.
Bassett, N. S., Oliver, M. H., Breier, B. H. & Gluckman, P. D. (1990) The effect
of maternal starvation on plasma insulin-like growth factor I concentrations in
the late gestation ovine fetus. Pediatr. Res. 27: 401– 404.
Behan, D. P., Potter, E., Sutton, S., Fischer, W., Lowry, P. J. & Vale, W. W. (1993)
Corticotropin-releasing factor-binding protein. A putative peripheral and cen-
tral modulator of the CRF family of neuropeptides. Ann. N.Y. Acad. Sci. 697:
1– 8.
Calogero, A. E., Gallucci, W. T., Chrousos, G. P. & Gold, P. W. (1988) Cate-
cholamine effects upon rat hypothalamic corticotropin-releasing hormone
secretion in vitro. J. Clin. Investig. 82: 839 – 846.
Campos, M. S., Barrionuevo, M., Alférez, M. J., Gómez-Ayala, A. E., Rodrı́guez-
Matas, M. C., Lopez Aliaga, I. & Lisbona, F. (1998) Interactions among iron,
calcium, phosphorus and magnesium in the nutritionally iron-deficient rat.
Exp. Physiol. 83: 771–781.
Cester, N., Staffolani, R., Rabini, R. A., Magnanelli, R., Salvolini, E., Galassi, R.,
Mazzanti, L. & Romanini, C. (1994) Pregnancy induced hypertension: a role
588S SUPPLEMENT
for peroxidation in microvillus plasma membranes. Mol. Cell. Biochem. 131:
151–155.
Challis, J. R., Richardson, B. S., Rurak, D., Wlodek, M. E. & Patrick, J. E. (1986)
Plasma adrenocorticotropic hormone and cortisol and adrenal blood flow
during sustained hypoxemia in fetal sheep. Am. J. Obstet. Gynecol. 155:
1332–1336.
Chrousos, G. P. (1998) Stressors, stress, and neuroendocrine integration of
the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann. N.Y.
Acad. Sci. 851: 311–335.
Chrousos, G. P. (1999) Reproductive placental corticotropin-releasing hor-
mone and its clinical implications. Am. J. Obstet. Gynecol. 180: S249 –S250.
Chrousos, G. P. & Gold, P. W. (1992) The concepts of stress and stress system
disorders. Overview of physical and behavioral homeostasis [published erra-
tum appears in J. Am. Med. Assoc. 268: 200]. J. Am. Med. Assoc. 267:
1244 –1252.
Cianfarani, S., Germani, D., Rossi, L., Argirò, G., Boemi, S., Lemon, M., Holly,
J. M. & Branca, F. (1998) IGF-I and IGF-binding protein-1 are related to
cortisol in human cord blood. Eur. J. Endocrinol. 138: 524 –529.
Coulter, C. L., Giraud, A. S., Hooper, S. B., Parker, L. & McMillen, I. C. (1990)
Fetal asphyxia stimulates an increase in fetal plasma catecholamines and
[Met]-enkephalin-arg6-phe7 in the late-gestation sheep fetus. J. Dev. Physiol.
14: 267–272.
Dallman, P. R. (1986) Biochemical basis for the manifestations of iron defi-
ciency. Annu. Rev. Nutr. 6: 13– 40.
De Amici, D., Gasparoni, A., Chirico, G., Ceriana, P., Bartoli, A., Ramajoli, I. &
Moretta, A. (1999) Natural killer cell activity and delivery: possible influence
of cortisol and anesthetic agents. A study on newborn cord blood. Biol.
Neonate 76: 348 –354.
Diez-Ewald, M. & Layrisse, M. (1968) Mechanisms of hemolysis in iron defi-
ciency anemia. Further studies. Blood 32: 884 – 894.
Ducsay, C. A. (1998) Fetal and maternal adaptations to chronic hypoxia:
prevention of premature labor in response to chronic stress. Comp. Biochem.
Physiol. A Mol. Integr. Physiol. 119: 675– 681.
Emanuel, R. L., Robinson, B. G., Seely, E. W., Graves, S. W., Kohane, I., Saltzman,
D., Barbieri, R. & Majzoub, J. A. (1994) Corticotrophin releasing hormone
levels in human plasma and amniotic fluid during gestation. Clin. Endocrinol.
40: 257–262.
Falkenberg, E. R., Davis, R. O, DuBard, M. & Parker, C. R., Jr. (1999) Effects
of maternal infections on fetal adrenal steroid production. Endocr. Res. 25:
239 –249.
Fowden, A. L., Szemere, J. Hughes, P. Gilmour, R. S. & Forhead, A. J. (1996)
The effects of cortisol on the growth rate of the sheep fetus during late
gestation. J. Endocrinol. 151: 97–105.
Gluckman, P. D. & Harding, J. E. (1997) Fetal growth retardation: underlying
endocrine mechanisms and postnatal consequences. Acta Paediatr. (suppl.)
422: 69 –72.
Gluckman, P. D., Johnson-Barrett, J. J., Butler, J. H., Edgar, B. W. & Gunn, T. R.
(1983) Studies of insulin-like growth factor-I and -II by specific radioligand
assays in umbilical cord blood. Clin. Endocrinol. 19: 405– 413.
Godfrey, K. M., Redman, C. W., Barker, D. J. & Osmond, C. (1991) The effect
of maternal anaemia and iron deficiency on the ratio of fetal weight to
placental weight. Br. J. Obstet. Gynaecol. 98: 886 – 891.
Goland, R. S., Wardlaw, S. L., Stark, R. I., Brown, L. S., Jr. & Frantz, A. G. (1986)
High levels of corticotropin-releasing hormone immunoactivity in maternal
and fetal plasma during pregnancy. J. Clin. Endocrinol. Metab. 63: 1199 –
1203.
Gülmezoglu, A. M., Mahomed, K., Hofmeyr, G. J., Nikodem, V. C. & Kramer, T.
(1996) Fetal and maternal catecholamine levels at delivery. J. Perinat. Med.
24: 687– 691.
Hedegaard, M., Henriksen, T. B., Secher, N. J., Hatch, M. C. & Sabroe, S. (1996)
Do stressful life events affect duration of gestation and risk of preterm
delivery? Epidemiology 7: 339 –345.
Hobel, C. J., Arora, C. P. & Korst, L. M. (1999a) Corticotrophin-releasing
hormone and CRH-binding protein. Differences between patients at risk for
preterm birth and hypertension. Ann. N.Y. Acad. Sci. 897: 54 – 65.
Hobel, C. J., Dunkel-Schetter, C., Roesch, S. C., Castro, L. C. & Arora, C. P.
(1999b) Maternal plasma corticotropin-releasing hormone associated with
stress at 20 weeks’ gestation in pregnancies ending in preterm delivery.
Am. J. Obstet. Gynecol. 180: S257–S263.
Hooper, S. B., Coulter, C. L., Deayton, J. M., Harding, R. & Thorburn, G. D.
(1990) Fetal endocrine responses to prolonged hypoxemia in sheep. Am. J.
Physiol. 259: R703–R708.
Institute of Medicine (1985) Preventing Low Birth Weight. National Academy
Press, Washington, DC.
Jackson, M. R., Mayhew, T. M. & Haas, J. D. (1988) On the factors which
contribute to thinning of the villous membrane in human placentae at high
altitude. II. An increase in the degree of peripheralization of fetal capillaries.
Placenta 9: 9 –18.
Jauniaux, E. & Burton, G. J. (1992) The effect of smoking in pregnancy on early
placental morphology. Obstet. Gynecol. 79: 645– 648.
Karalis, K., Goodwin, G. & Majzoub, J. A. (1996) Cortisol blockade of proges-
terone: a possible molecular mechanism involved in the initiation of human
labor. Nat. Med. 2: 556 –560.
Kramer, M. S. (1998) Socioeconomic determinants of intrauterine growth
retardation. Eur. J. Clin. Nutr. 52: S29 –S33.
Kramer, M. S., McLean, F. H., Eason, E. L. & Usher, R. H. (1992) Maternal
nutrition and spontaneous preterm birth. Am. J. Epidemiol. 136: 574 –583.
Kramer, M. S., Platt, R., Yang, H., Joseph, K. S., Wen, S. W., Morin, L. & Usher,
R. H. (1998) Secular trends in preterm birth: a hospital-based cohort study.
J. Am. Med. Assoc. 280: 1849 –1854.
Kurki, T., Sivonen, A., Renkonen, O. V., Savia, E. & Ylikorkala, O. (1992) Bac-
terial vaginosis in early pregnancy and pregnancy outcome. Obstet. Gynecol.
80: 173–177.
Li, J., Saunders, J. C., Gilmour, R. S., Silver, M. & Fowden, A. L. (1993)
Insulin-like growth factor-II messenger ribonucleic acid expression in fetal
tissues of the sheep during late gestation: effects of cortisol. Endocrinology
132: 2083–2089.
Lin, C. C. & Santolaya-Forgas, J. (1998) Current concepts of fetal growth
restriction: part I. Causes, classification, and pathophysiology. Obstet. Gy-
necol. 92: 1044 –1055.
Linton, E. A., Behan, D. P., Saphier, P. W. & Lowry, P. J. (1990) Corticotropin-
releasing hormone (CRH)-binding protein: reduction in the adrenocorticotrop-
in-releasing activity of placental but not hypothalamic CRH. J. Clin. Endocri-
nol. Metab. 70: 1574 –1580.
Linton, E. A., Wolfe, C. D., Behan, D. P. & Lowry, P. J. (1988) A specific carrier
substance for human corticotrophin releasing factor in late gestational ma-
ternal plasma which could mask the ACTH-releasing activity. Clin. Endocrinol.
28: 315–324.
Lobel, M., Dunkel-Schetter, C. & Scrimshaw, S.C.M. (1992) Prenatal maternal
stress and prematurity: a prospective study of socioeconomically disadvan-
taged women. Health Psychol. 11: 32– 40.
Majzoub, J. A. & Karalis, K. P. (1999) Placental corticotropin-releasing hor-
mone: function and regulation. Am. J. Obstet. Gynecol. 180: S242–S246.
McCullough, R. E. & Reeves, J. T. (1977) Fetal growth retardation and in-
Downloaded from jn.nutrition.org by guest on March 4, 2015
creased infant mortality at high altitude. Arch. Environ. Health 32: 36 –39.
McLean, M., Bisits, A., Davies, J., Woods, R., Lowry, P. & Smith, R. (1995) A
placental clock controlling the length of human pregnancy. Nat. Med. 1:
460 – 463.
Milley, J. R. (1988) Uptake of exogenous substrates during hypoxia in fetal
lambs. Am. J. Physiol. 254: E572–E578.
Milley, J. R. (1997) Ovine fetal metabolism during norepinephrine infusion.
Am. J. Physiol. 273: E336 –E347.
Mirlesse, V., Frankenne, F., Alsat, E., Poncelet, M., Hennen, G. & Evain-Brion, D.
(1993) Placental growth hormone levels in normal pregnancy and in preg-
nancies with intrauterine growth retardation. Pediatr. Res. 34: 439 – 442.
Moore, L. G., Jahnigen, D., Rounds, S. S., Reeves, J. T. & Grover, R. F. (1982a)
Maternal hyperventilation helps preserve arterial oxygenation during high-
altitude pregnancy. J. Appl. Physiol. 52: 690 – 694.
Moore, L. G., Rounds, S. S., Jahnigen, D., Grover, R. F. & Reeves, J. T. (1982b)
Infant birth weight is related to maternal arterial oxygenation at high altitude.
J. Appl. Physiol. 52: 695– 699.
Nieto-Dı́az, A., Villar, J., Matorras-Weinig, R. & Valenzuela-Ruı̀z, P. (1996) In-
trauterine growth retardation at term: association between anthropometric
and endocrine parameters. Acta Obstet. Gynecol. Scand. 75: 127–131.
Nordentoft, M., Lou, H. C., Hansen, D., Nim, J., Pryds, O., Rubin, P. & Hemming-
sen, R. (1996) Intrauterine growth retardation and premature delivery: the
influence of maternal smoking and psychosocial factors. Am. J. Public Health
86: 347–354.
Ojasoo, T., Doré, J. C., Gilbert, J. & Raynaud, J. P. (1988) Binding of steroids
to the progestin and glucocorticoid receptors analyzed by correspondence
analysis. J. Med. Chem. 31: 1160 –1169.
Oliver, M. H., Harding, J. E, Breier, B. H., Evans, P. C. & Gluckman, P. D. (1993)
Glucose but not a mixed amino acid infusion regulates plasma insulin-like
growth factor-I concentrations in fetal sheep. Pediatr. Res. 34: 62– 65.
Parker, C. R., Jr., Hankins, G. D., Carr, B. R., Gant, N. F., MacDonald, P. C. &
Porter, J. C. (1986) Prolactin levels in umbilical cord serum and its relation
to fetal adrenal activity in newborns of women with pregnancy-induced hy-
pertension. Pediatr. Res. 20: 876 – 878.
Perkins, A. V., Linton, E. A., Eben, F., Simpson, J., Wolfe, C. D. & Redman, C. W.
(1995) Corticotrophin-releasing hormone and corticotrophin-releasing hor-
mone binding protein in normal and pre-eclamptic human pregnancies. Br. J.
Obstet. Gynaecol. 102: 118 –122.
Petraglia, F., Benedetto, C., Florio, P., D’Ambrogio, G., Genazzani, A. D., Marozio,
L. & Vale, W. (1995) Effect of corticotropin-releasing factor-binding protein
on prostaglandin release from cultured maternal decidua and on contractile
activity of human myometrium in vitro. J. Clin. Endocrinol. Metab. 80: 3073–
3076.
Poranen, A. K., Ekblad, U., Uotila, P. & Ahotupa, M. (1996) Lipid peroxidation
and antioxidants in normal and pre-eclamptic pregnancies. Placenta 17:
401– 405.
Rao, J. & Jagadeesan, V. (1996) Lipid peroxidation and activities of antioxidant
enzymes in iron deficiency and effect of carcinogen feeding. Free Radic. Biol.
Med. 21: 103–108.
Rasmussen, K. (2001) Is there a causal relationship between iron deficiency or
iron-deficiency anemia and weight at birth, length of gestation and perinatal
mortality? J. Nutr. 131: 590S– 603S.
Riley, S. C., Walton, J. C., Herlick, J. M. & Challis, J. R. (1991) The localization
and distribution of corticotropin-releasing hormone in the human placenta
and fetal membranes throughout gestation. J. Clin. Endocrinol. Metab. 72:
1001–1007.
Sabrevilla, L. A., Romero, I., Kruger, F. & Whittembury, J. (1968) Low estrogen
 IRON-DEFICIENCY ANEMIA AND PRETERM DELIVERY
excretion during pregnancy at high altitude. Am. J. Obstet. Gynecol. 102:
828 – 833.
Sandman, C. A., Wadhwa, P. D., Chicz-DeMet, A., Dunkel-Schetter, C. & Porto,
M. (1997) Maternal stress, HPA activity, and fetal/infant outcome. Ann.
N.Y. Acad. Sci. 814: 266 –275.
Sandman, C. A., Wadhwa, P., Glynn, L., Chicz-Demet, A., Porto, M. & Garite, T. J.
(1999) Corticotrophin-releasing hormone and fetal responses in human
pregnancy. Ann. N.Y. Acad. Sci. 897: 66 –75.
Schocknecht, P. A., McGuire, M. A., Cohick, W. S., Currie, W. B. & Bell, A. W.
(1992) The effect of placental lactogen infusion on serum IGF-1 and IG-
FBP-2 concentrations in the late gestation ovine fetus. J. Anim. Sci. 70: 212
(abs).
Scholl, T. O., Hediger, M. L., Fischer, R. L. & Shearer, J. W. (1992) Anemia vs
iron deficiency: increased risk of preterm delivery in a prospective study.
Am. J. Clin. Nutr. 55: 985–988.
Scholl, T. O. & Stein, T. P. (2000) Oxidative stress during gestation and
adverse pregnancy outcome. FASEB J. 14: A725 (abs.).
Smith, R. (1998) Alterations in the hypothalamic pituitary adrenal axis during
pregnancy and the placental clock that determines the length of parturition. J.
Reprod. Immunol. 39: 215–220.
Smith, R. (1999) The timing of birth. Sci. Am. (March): 68 –75.
Stratakis, C. A., Gold, P. W. & Chrousos, G. P. (1995) Neuroendocrinology of
stress: implications for growth and development. Horm. Res. 43: 162–7.
Vetore, L. & Tedesco, C.H.J.G. (1975) Membrane lipid peroxidation in hypo-
chromic red blood cells. Haematologica 60: 250 –258.
Villar, J. & Belizan, J. M. (1982) The relative contribution of prematurity and
fetal growth retardation to low birth weight in developing and developed
societies. Am. J. Obstet. Gynecol. 143: 793–798.
Viteri, F. E. (1994) The consequences of iron deficiency and anemia in preg-
nancy. Adv. Exp. Med. Biol. 352: 127–139.
Vives Corrons, J. L., Miguel-Garcı́a, A., Pujades, M. A., Miguel-Sosa, A., Cambi-
azzo, S., Linares, M., Dibarrart, M. T. & Calvo, M. A. (1995) Increased
susceptibility of microcytic red blood cells to in vitro oxidative stress. Eur. J.
Haematol. 55: 327–331.
West, K. P., Jr., Christian, P., Katz, J., Khatry, S. K., Pradhan, E. K. & Shrestha,
S. R. (2000) ␤-Carotene reduces the elevated risk of maternal mortality
associated with smoking and alcohol consumption in Nepal. FASEB J. 14:
A559 (abs.).
Wolfe, C. D., Patel, S. P., Linton, E. A., Campbell, E. A., Anderson, J., Dornhorst,
A., Lowry, P. J. & Jones, M. T. (1988) Plasma corticotrophin-releasing
factor (CRF) in abnormal pregnancy. Br. J. Obstet. Gynaecol. 95:1003–1006.
Woods, R. J., Grossman, A., Saphier, P., Kennedy, K., Ur, E., Behan, D., Potter,
E., Vale, W. & Lowry, P. J. (1994) Association of human corticotropin-
589S
releasing hormone to its binding protein in blood may trigger clearance of the
complex. J. Clin. Endocrinol. Metab. 78: 73–76.
Yu, V. Y. & Wood, E. C. (1987) Prematurity. Churchill Livingstone, Edinburgh,
Scotland.
DISCUSSION
Participants: Rasmussen, Allen.
Dr. Rasmussen: The low birth weight or intrauterine
growth retardation rate varies considerably worldwide as
does the rate of iron deficiency, but the preterm rate does
not vary a lot from country to country. So, I am having
trouble linking those two. If I have iron status that varies a
lot and I have a preterm rate that is not so variable, I have
trouble figuring out how the two of those might be associ-
ated. Can you speak to that at all?
Dr. Allen: I agree. There is about double the preterm rate
in developing countries, but you would think if iron deficiency
caused that much preterm, you would see an enormous pre-
term rate. Remember that preterm rates are counted only in
babies weighing less than 2500 g. My suspicion is that there
are a lot of children born between 2500 and 3000 g or 3100 g
who might be slightly preterm or preterm. They might be born
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earlier than usual and, therefore, have a slightly lower birth
weight. You will not pick it up in low-birth-weight statistics.
Dr. Rasmussen: No, but if you use decent low birth weights
and decent statistics on intrauterine growth retardation, low
birth weight varies significantly around the world when pre-
term is much more constant.
Dr. Allen: Right, but I am saying that it does not have to
be preterm by that much. I think we lack really good data,
especially from places with a high prevalence of iron defi-
ciency, such as south Asia. So, I just do not think we quite
know yet. I agree that it is something that has to be sorted out.