Iron status during pregnancy: setting the stage for mother and infant

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{at}umdnj.edu.

ABSTRACT

Supplementation with iron is generally recommended during pregnancy to meet the iron needs of both mother and fetus. When detected early in pregnancy, iron deficiency anemia (IDA) is associated with a > 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 supplementation 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 indicator of an expanded maternal plasma volume. High levels of hemoglobin, 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 considered 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 increased 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.

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 pregnancy 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 increased 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 controversy.

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 (>80 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 reproductive 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 increased 2-fold or more for those women who are minorities, below the poverty level or with < 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 < 50% of women do not have adequate iron stores for pregnancy (1, 3). Because the iron required for pregnancy (3–4 mg/d) is substantial, risk of iron deficiency and IDA should increase with gestation. However, the prevalence of anemia 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 > 4-fold from the 1^st to the 3^rd trimester in the low-income women monitored as part of pregnancy nutritional surveillance by the CDC (3). In the Camden Study where the cohort is mostly minority, current data (2000–2004) suggest that the prevalence of anemia increases > 6-fold from 6.7% (1^st trimester) to 27.3% (2^nd trimester) to 45.6% in the 3^rd trimester. Only a fraction of anemic women in Camden have iron deficiency anemia. Based on low hemoglobin for gestation by CDC criteria plus low ferritin (<12), iron deficiency anemia in Camden gravidas is lower—1.8% in 1^st trimester, to 8.2% in 2^nd trimester, and 27.4% in 3^rd trimester (Figure 1). Thus, anemia and IDA are not synonymous, even among low-income minority women in their reproductive years.

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FIGURE 1.. Anemia and Iron Deficiency Anemia (IDA) Camden Study, 2000–2004.

 
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 folate/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 simultaneously. Hemoglobin and hematocrit decline throughout the 1^st and 2^nd trimesters, reach their lowest point late in the second to early in the 3^rd 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 anemia 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 corpuscular volume (MCV) and diet in women with and without IDA that either were not present or were greatly diminished during the 3^rd trimester. At entry, women with iron deficiency anemia had an MCV that was significantly lower (6.5 femtoliters) than other women. During the 3^rd 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 less (5 mg less) because of the difference in energy. During the 3^rd 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 3^rd 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 3^rd trimester, risk of preterm delivery 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 between 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 1^st or 2^nd 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 doubled, for women with milder anemia, risk of preterm delivery was increased between 10%–40%. During the 3^rd trimester the association 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 anemia on preterm delivery that was the most detectable during the 1^st 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 > 2-fold in moderately anemic women (90–99 g/L) and > 3-fold in those who were severely anemic (<90 g/L) during the 1^st trimester. At midpregnancy and late in the 3^rd trimester, the influence of maternal 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 pregnancy 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 3^rd 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) suggested 3 potential mechanisms whereby maternal IDA might give rise to preterm delivery: hypoxia, oxidative stress, and infection. 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 delivery. Increased oxidative stress in iron deficient women that was not offset by endogenous or dietary antioxidants could damage the maternal-fetal unit and result in preterm delivery. With reduced 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 studies, 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 pregnant women, all WIC participants, none anemic, who were enrolled 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 ± 3.8 wk gestation. Cut-points, which rendered women ineligible for the trial, were hemoglobin < 110g/L and serum ferritin < 20 µg/L. At weeks 28 and 38, women who were not anemic or iron deficient continued on either the iron or placebo arm. At those points women with serum ferritin < 12 µg/L received 60 mg iron/d and those with ferritin between 12 and < 20 µg/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 < 12 µg/L) and with IDA (Hgb < 110 g/L, ferritin < 12 µg/L) at week 28 were significantly lower among the iron supplemented. Supplemented women had significantly longer gestation durations (+ 0.6 wk), and increased infant birth weight (+ 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 supplementation but had been reckoned solely from the mother’s last menstrual 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 received either vitamin A (1000 µg retinol equivalents) alone (control), vitamin A plus folic acid (400 µg), 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 comparison 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.

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, < 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 supplemental 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 1^st and 2^nd 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 increased 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 hemoglobin along with anemia. During the 1^st trimester women with hemoglobin levels exceeding 130g/L showed no increase in the risk of SGA births but had a > 2-fold increases in preterm delivery and infant low birth weight. There were few such women and increased risks were usually not statistically significant. 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 > 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 hemoglobin and poor fetal growth. Women randomized to the selective group received iron supplements only when hematocrit fell below 30% or hemoglobin below 100 g/L on 2 consecutive visits after week 33. In comparison to selective supplementation, routine supplementation with iron halted the decline in hematocrit by week 20 and did not alter infant birth weight, whereas gestation duration was increased significantly (+ 0.2 wk). Interestingly, 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 1^st trimester (23). A recent study from the Netherlands, wherein a cohort of 240 women was monitored from before conception to delivery, underscores this point. Gravidas with an early pregnancy fetal loss had a less profound decline in hematocrit from before conception 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 3^rd trimester of pregnancy (>41 ng/mL) have a greatly increased risk of preterm and very preterm delivery that has been attributed to intrauterine 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 3^rd trimester ferritin. In the 3^rd trimester the situation reversed, thus implicating plasma volume 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, (Fe²⁺ Fe³⁺) 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 overload, 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 (>107 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 controls 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 3^rd 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 3^rd 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 data from > 1023 gravidas from Camden. Controlling for potential confounding variables (age, BMI, parity, ethnicity, smoking, 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 3^rd trimester (AOR 2.9; 95% CI 1.27–6.95) (32). This positive 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 pregnancy 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, routine 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 administration of an iron supplement (100 mg/d as fumarate) with vitamin C (500 mg/d as ascorbate) during the 3^rd trimester of pregnancy increased measures of maternal iron status. An indicator 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. 350 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 (>59 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 3^rd trimester a similar relation was found between high transferrin saturation (>21.7%) and 8 OH-dG in the highest tertile (AOR = 3.3; 95% CI 1.28–8.11). Thus, preliminary findings suggest an association between increased 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 further. 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 inflammation, 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.

ACKNOWLEDGMENTS

The author has no personal or financial conflict of interest related to this project.

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