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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)
KEY WORDS: ● iron deficiency ● anemia ● preterm ● low birth weight ● pregnancy
● corticotropin-releasing hormone
The article by Rasmussen (2001) in this supplement re- information about the biological mechanisms involved in pre-
views the strength and plausibility of the evidence that iron- term delivery and intrauterine growth retardation (IUGR)3
deficiency anemia or anemia is the cause of adverse birth and suggests ways in which these may be affected by anemia or
outcomes. Although there are numerous reports of an associ- iron deficiency. It is intended to provide information that will
ation between maternal hemoglobin and both lower birth be useful for planning which hormones and metabolites should
weight and preterm delivery, Rasmussen concludes that evi- be measured in future studies of the role of iron deficiency and
dence is insufficient to prove that iron deficiency plays a causal iron-deficiency anemia in pregnancy outcome.
role in poor pregnancy outcome. To some extent, this lack of The review starts with a summary, based on the Rasmussen
evidence is due to the inadequate design of published studies. review, of what is known about the possible effects of iron
The purpose of this paper is to explore the biological deficiency and iron-deficiency anemia on infant size at birth
mechanisms through which anemia or iron deficiency might and duration of gestation. The prevalence of IUGR and pre-
cause poor fetal growth and preterm delivery, regardless of term delivery is described, with a comparison of the risk factors
whether a causal link has been proven. Because of the complex for these conditions. This is followed by a description of the
hormonal and physiological factors that affect pregnancy out- biological mechanisms involved in the normal delivery pro-
come and the virtual lack of any studies of the effects of iron cess, including the central role of corticotropin-releasing hor-
deficiency on these factors, the biological mechanisms pro- mone (CRH) in determining the duration of gestation and the
posed below are hypothetical. This article summarizes current association of other hormones with fetal growth. Finally,
mechanisms are proposed that might underline iron’s effects
1
on these processes, increasing the risk of preterm delivery and
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 low birth weight.
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
3
Hopkins School of Public Health, Baltimore, MD. Abbreviations used: ACTH, adrenocorticotropic hormone; CRH, cortico-
2
This article was commissioned by the World Health Organization (WHO). tropin-releasing hormone; CRH-BP, CRH-binding protein; IGF, insulin-like growth
The views expressed are those of the author alone and do not necessarily reflect factor; IUGR, intrauterine growth retardation; LC, locus ceruleus; NE, norepineph-
those of WHO. rine;
581S
582S SUPPLEMENT
Associations between iron-deficiency anemia and and morbidity in industrialized countries, in which the prev-
pregnancy outcome alence has not fallen in the last few decades. In fact, in a large,
carefully conducted Canadian study, the rate of preterm births
Nonintervention studies. In her review, Rasmussen sum- over the past 20 years increased from 6.6 to 9.8% for ⬍37 wk,
marizes the results of 54 nonintervention studies that exam- 1.7 to 2.3% for ⬍34 wk and 1.0 to 1.2% for ⬍32 wk (Kramer
ined associations between hemoglobin or hematocrit and preg- et al. 1998). Although half of the apparent increase in prev-
nancy outcome. Of these, 44 analyzed associations among alence was due to earlier use of ultrasound dating, other factors
hemoglobin or hematocrit, birth weight and percentage of low such as preterm induction of labor, use of cocaine and an
birth weight (ⱕ2500 g) deliveries. In 26 of the 44, anemia, increase in the number of pregnant unmarried women have
lower hemoglobin or hematocrit, or low ferritin concentra- tended to increase the prevalence.
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 Risk factors for low birth weight and preterm delivery:
explain these observed associations between lower birth similarities and differences
weight and anemia because gestational age was assessed in only Nonnutritional causes of fetal growth retardation include
10 of the 44 studies. In 5 of these 10 (2 in Papua New Guinea, hemorrhage, multiple births, uterine and placental abnormal-
1 in India, 1 in Hong Kong and 1 in the United States), ities, parental size and genetics, and major congenital malfor-
anemia was associated with a shorter gestation period. In the mations. These explain up to 50% of the variance in birth
U.S. study on adolescents of low socioeconomic status, pre- weight in both developed and developing countries (Villar and
term delivery explained all of the lower birth weight associated Belizan 1982). In developing countries, more IUGR is due to
with iron-deficiency anemia when other potential confounders low maternal weight and height (undernutrition during the
were controlled for by regression analysis (Scholl et al. 1992). mother’s development), low pregnancy weight gain (which is
In 21 of the 54 nonintervention studies summarized by
Lobel et al. 1992, Nordentoft et al. 1996). One of the more produce dehydroepiandrosterone sulfate, which is converted to
certain risk factors for preterm delivery, maternal infection, estrogen by the placenta. Changes occur as a result of the
has been implicated in up to 40% of cases (Kurki et al. 1992). increase in estrogen concentrations. The cells of the myome-
Thus, there is substantial overlap between the risk factors trium synthesize connexin molecules, which move to the cell
for preterm delivery and IUGR. Moreover, as will be discussed membrane and connect the cells electrically so that they will
below, there are strong links in the underlying biological contract synchronously during labor; muscle cells in the uterus
mechanisms associated with these two outcomes. produce large numbers of oxytocin receptors, necessary for this
hormone to cause contraction of the cells during labor; in
Biological mechanisms involved in the normal delivery addition, the synthesis of prostaglandins by placental tissues
process overlying the cervix is increased, which induces the produc-
tion of enzymes in the cervix that digest collagen and make
Our understanding of the biological mechanisms that con- the cervix flexible during delivery of the fetus.
trol the timing of delivery is relatively recent, with major Despite the high concentrations of CRH in maternal
advances occurring in the mid-1990s (Smith 1998). As a plasma, maternal plasma concentrations of ACTH and corti-
result, there is relatively little information on factors that sol remain relatively normal during pregnancy. This is proba-
affect these mechanisms and virtually none on nutritional bly due to CRH-binding protein (CRH-BP), which neutralizes
factors. To some extent, the lack of information is due to the CRH earlier in pregnancy. The mRNA for CRH-BP is ex-
ethical difficulties of doing intervention trials that could in- pressed in the placenta, decidua, myometrium and fetal mem-
fluence delivery in humans. Animal models have been useful, branes during pregnancy and reduces the amount of active
and the basic mechanism underlying parturition in sheep had CRH in the maternal circulation (Linton et al. 1988). How-
been identified by the mid-1980s. However, the ovine mech- ever, during the third trimester, the concentration of CRH-BP
anisms and those in some primates are different from those in declines to about one third the peak concentration, falling by
28 wk (but not later), during the third trimester of twin plasma IGF-1 in rodents also correlates with fetal growth
pregnancies, and in women with pregnancy-induced hyperten- (Mirlesse et al. 1993). Most newborn IUGR infants have low
sion, premature rupture of the membranes or preterm labor levels of IGF-1. In a comparison of 15 normal newborns and
(with higher concentrations from at least as early as 28 wk). In 30 with IUGR, the IUGR group had significantly lower con-
some of the pregnancies, CRH concentrations were elevated centrations of IGF-1 and higher concentrations of IGF-bind-
11 wk before any other symptoms appeared. ing protein-3 (Cianfarani et al. 1998). In a case-control study
Normal CRH concentrations do not completely guarantee of 76 full-term deliveries, of which 31 were IUGR, cord blood
a normal delivery date because fetal infections and other concentrations of IGF-1, insulin and thyroid-stimulating hor-
problems can cause early delivery regardless of CRH, and there mone were lower in the IUGR group, but higher concentra-
is considerable interindividual variability in normal concen- tions of growth hormone were present (Nieto-Dı́az et al.
trations. However, abnormal CRH concentrations are highly 1996).
predictive of the duration of gestation. Cortisol inhibits longitudinal growth of the sheep fetus in
Other actions of CRH. As will be explained in more late gestation (Fowden et al. 1996) and probably plays a major
detail below, CRH plays a major role in both the maternal and role in regulating growth at this time. In sheep, preventing the
fetal stress systems. It has been estimated that during a stressful cortisol surge by fetal adrenalectomy abolished the normal
event, the amount of CRH released is so high and the avail- slowing of growth at term, and infusing cortisol earlier in
able time for exposure to CRH-BP is so low that maternal gestation lowered the rate of longitudinal growth to that
CRH will not be completely quenched by CRH-BP. This normally seen in late pregnancy (Fowden et al. 1996). Over
means that CRH can still act as a stress hormone during the entire gestation period, mean plasma cortisol concentra-
pregnancy (Linton et al. 1990). Additional actions of CRH tions accounted for 40 –50% of the variation in fetal crown-
include the following: stimulation of prostaglandin F2␣ and rump length increment. Cortisol suppresses the production of
prostaglandin E2 production by fetal membranes; potentiation IGF-2 in fetal sheep (Li et al. 1993). It also appears to switch
Hormones that influence fetal growth There have been no studies of the effect of iron deficiency
or anemia on the biological mechanisms that can affect pre-
The clinical pattern of poor fetal growth depends on the term delivery or fetal growth. In fact, only one study was found
cause of the poor growth, its timing and its duration. Earlier in which any hormonal differences were examined in relation
undernutrition tends to cause symmetric growth retardation, to maternal iron status and hemoglobin concentrations in
whereas later undernutrition causes the proportions of the pregnancy. In population studies, placental size is inversely
fetus to be more asymmetric. Many factors have been associ- related to hemoglobin concentration across a wide range of
ated with increased risk of fetal growth retardation, as re- hemoglobin values (Godfrey et al. 1991). By 18 wk of preg-
viewed elsewhere (Lin and Santolaya-Forgas 1998). nancy, placental volume may already be inversely correlated
The insulin-like growth factor (IGF) system is probably the with maternal hemoglobin and serum ferritin concentrations,
most important with respect to fetal growth, and IGF-1 is the even in industrialized countries. On the basis of this observa-
most important hormone (Gluckman and Harding 1997). Fe- tion, associations between maternal hemoglobin and iron sta-
tal IGF-1 is secreted in response to fetal glucose concentra- tus and factors known to affect placental size, i.e., human
tions (Oliver et al. 1993). IGF directs nutrients to insulin- chorionic gonadotropin and human placental lactogen, were
sensitive tissues, promoting glycogen and fat storage in muscle, assessed during the first trimester of pregnancy in 175 women
liver and adipose tissue. Substrate availability is the main who were consulting about pregnancy termination. The aver-
determinant of fetal IGF-1 levels (Gluckman et al. 1983). In age duration of gestation was 68 d. Maternal hemoglobin was
animal models, maternal starvation quickly lowers fetal IGF-1 significantly negatively correlated with the levels of human
concentrations and subsequently fetal growth (Bassett et al. chorionic gonadotropin and human placental lactogen across
1990). Maternal IGF-1, IGF-2 and insulin do not cross the the normal hemoglobin range. Although serum ferritin con-
placenta but they may affect placental function; maternal centrations were low in 21% of the women, there was no
IRON-DEFICIENCY ANEMIA AND PRETERM DELIVERY 585S
correlation with the hormone concentrations. The authors directly linked to the stress system, and each is profoundly
suggest that the oxygen content of maternal blood may have influenced by the effectors of the stress response.”
had an important influence on the development of the pla- In the nonpregnant individual, the stress system is located
centa and subsequently on human chorionic gonadotropin and in both the central nervous system and the periphery. Its role
human placental lactogen concentrations. There is no reason is to create physiological changes that redirect energy, oxygen
to believe that increased human chorionic gonadotropin or and nutrients to the central nervous system and stressed body
human placental lactogen concentration would have an ad- sites, and behavioral changes such as fight-or-flight responses.
verse effect on pregnancy outcome. The stress system is complex; its description is beyond the
Because virtually nothing is known about the effects of iron scope of this review. More detailed reviews are available
deficiency or anemia on the biological mechanisms that reg- (Chrousos 1998, Chrousos et al. 1992, Stratakis et al. 1995).
ulate the duration of gestation and fetal growth, the discussion Systems of relevance here include the following: the CRH
in this section focuses mainly on other factors and illnesses system, which is found throughout the brain (particularly in
that are known to influence these mechanisms and that could the hypothalamus and the medulla) and works synergistically
plausibly explain any effects of anemia or iron deficiency. The with arginine-vasopressin neurons of the hypothalamus; the
postulated biological mechanisms are as follows. LC/NE system in the medulla and pons of the brain, and their
Iron deficiency or anemia may increase the stress hor- peripheral effectors including the hypothalamic-pituitary-ad-
mones, norepinephrine and cortisol. Iron deficiency in- renal axis; the efferent sympathetic/adrenomedullary system;
creases norepinephrine (NE) concentrations (Dallman 1986), and components of the parasympathetic system, which coor-
as does hypoxia (Gülmezoglu et al. 1996). Norepinephrine is a dinate the stress response.
strong stimulus for the release of CRH (Calogero et al. 1988) CRH is the primary regulator of the hypothalamic-pitu-
and cortisol. The CRH and locus ceruleus/NE (LC/NE) sym- itary-adrenal axis, and administration of CRH can produce
pathetic systems respond similarly to many of the same neu- most of the physiological and behavioral responses to stress,
and remained higher during at least the next 12 h (Ducsay a significant amount of variance in CRH at 28 –30 wk gesta-
1998). Before 126 d of gestation in a similar hypoxic sheep tion, with CRH at 18 –20 wk controlled for. The authors
model (the normal duration of gestation in the sheep is ⬃150 concluded that maternal stress and CRH concentrations may
d), there was no significant effect of hypoxia on fetal plasma be good markers for risk of preterm birth.
noradrenaline concentrations, but after this, concentrations In a prospective study of 8719 Danish women with single-
increased more than sixfold compared with controls, and ton pregnancies, those who reported one or more highly stress-
adrenaline increased fourfold (Coulter et al. 1990). In a sheep ful life events had a 1.76 times greater risk of preterm delivery
model, fetal hypoxia also reduced the transport of amino acids than those without stressful events (Hedegaard et al. 1996).
to the fetus (Milley 1988). The association was strongest for events occurring between 16
Stress is associated with IUGR. CRH is released from the and 30 wk. Sandman et al. (1997) found that higher maternal
hypothalamus in all individuals in response to stress in addi- stress at 28 –30 wk of gestation was a significant predictor of
tion to being produced by the placenta during pregnancy. both gestational age at birth and birth weight. Maternal stress
During pregnancy, the normal stress signal may be amplified by in the third trimester was associated with higher levels of
the placental release of CRH. Placental CRH and hypotha- maternal ACTH and cortisol.
lamic CRH are similar in structure. Plasma concentrations are Pregnancy outcome in other hypoxic situations. Pregnant
nondetectable in nonpregnant adults. women who are used to living at high altitude have a substan-
Is placental CRH also stimulated by chronic fetal stress? To tially higher incidence of IUGR but not of preterm deliveries
investigate this question, CRH was measured in the cord blood (McCullough and Reeves 1977, Moore et al. 1982b, Sabrevilla
of IUGR (at 26 – 40 wk) and normal infants matched by et al. 1968). The same is true in sheep kept in conditions of
gestational age (Goland et al. 1986). The mean umbilical cord chronic high altitude hypoxia (Ducsay 1998). The higher risk
plasma CRH concentration was 206 ⫾ 26 pmol/L in the of IUGR occurs even though there are maternal and fetal
IUGR infants and 49 ⫾ 17 pmol/L in the appropriate-for- adaptations to high altitude, including maternal hyperventi-
mechanism thought to cause preeclampsia, pregnancy-induced vagina. Early bacterial vaginosis (before 16 wk) is associated
hypertension and pregnancy-induced diabetes (Cester et al. with a relative risk of preterm delivery of 5–7.5. If this con-
1994, Poranen et al. 1996). Interest is increasing in the pos- dition occurs after 26 wk, the risk is 1.4 –1.9 (Kurki et al.
sibility that antioxidant nutrients might improve pregnancy 1992). There is potential for CRH to regulate inflammatory
outcome by reducing oxidative stress (Scholl and Stein 2000, responses and vice versa. The cytokine interleukin-1 stimu-
West et al. 2000). lates production of CRH, and CRH in turn regulates cytokine
The lipids of the brush border membrane of the placental production by immune effector cells. Because maternal stress is
syncitioblast are susceptible to peroxidation by being in con- associated with preterm birth, abnormalities in the regulation
tact with oxidants in the maternal blood. Scavengers of highly of CRH and the production of inflammatory cytokines may be
reactive oxygen species, including antioxidant enzymes such as a mechanism that could form the pathophysiological basis for
superoxide dismutase, catalase and glutathione reductase, pro- this association.
tect against peroxidation. These enzymes inhibit lipid peroxi- Falkenberg et al. (1999) examined the effect of maternal
dation. Placental oxidant-antioxidant imbalance might cause infections on the fetal hypothalamic-pituitary-adrenal axis.
release of products of lipid peroxidation into the fetal circula- Subjects were 361 women with normal pregnancy (including
tion with subsequent damage to endothelial cell membranes. some with preterm delivery) and 110 with infections. Cord
Iron deficiency may cause increased oxidative stress because blood was analyzed at delivery, which occurred between 24
it causes erythrocytes to be more susceptible to oxidative and 44 wk of gestation. The infants born to women with
damage. Erythrocytes are normally protected from oxidative infections were born 1.5 wk earlier, and cord blood concen-
stress caused by free radicals released from the potentially trations of cortisol and dehydroepiandrosterone sulfate were
dangerous combination of iron and oxygen. Mechanisms that significantly higher. The authors suggested that products of the
achieve this protection include superoxide dismutase, reduced activated immune system of mothers with infections may have
glutathione and catalase. However, microcytic erythrocytes crossed the placenta and activated the fetal hypothalamic-
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(abs).
growth retardation rate varies considerably worldwide as
Scholl, T. O., Hediger, M. L., Fischer, R. L. & Shearer, J. W. (1992) Anemia vs does the rate of iron deficiency, but the preterm rate does
iron deficiency: increased risk of preterm delivery in a prospective study. not vary a lot from country to country. So, I am having
Am. J. Clin. Nutr. 55: 985–988. trouble linking those two. If I have iron status that varies a
Scholl, T. O. & Stein, T. P. (2000) Oxidative stress during gestation and
adverse pregnancy outcome. FASEB J. 14: A725 (abs.). lot and I have a preterm rate that is not so variable, I have
Smith, R. (1998) Alterations in the hypothalamic pituitary adrenal axis during trouble figuring out how the two of those might be associ-
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Smith, R. (1999) The timing of birth. Sci. Am. (March): 68 –75. Dr. Allen: I agree. There is about double the preterm rate
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stress: implications for growth and development. Horm. Res. 43: 162–7. caused that much preterm, you would see an enormous pre-
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who might be slightly preterm or preterm. They might be born