Iron Metabolism in Pregnancy

Iron absorption from the duodenum is limited to its ferrous (divalent) state, the form found in
iron supplements. Ferric (trivalent) iron from vegetable food sources must first be converted
to the divalent state by the enzyme ferric reductase. If body iron stores are normal, only about
10 percent of ingested iron is absorbed, most of which remains in the mucosal cells or
enterocytes until sloughing leads to excretion in the feces (1 mg/day).[85] Under conditions of
increased iron needs, the fraction of iron absorbed increases. After absorption, iron is released
from the enterocytes into the circulation, where it is carried bound to transferrin to the liver,
spleen, muscle, and bone marrow. In those sites, iron is freed from transferrin and
incorporated into hemoglobin (75 percent of iron), and myoglobin, or stored as ferritin and
hemosiderin.[85] Menstruating women have about half the iron stores of men, with total body
iron of 2 to 2.5 g and iron stores of only 300 mg. Before pregnancy, 8 to 10 percent of
women in Western nations have iron deficiency.[85]

The iron requirements of gestation are about 1,000 mg. This includes 500 mg used to increase
the maternal RBC mass (1 ml of erythrocytes contains 1.1 mg iron), 300 mg transported to
the fetus, and 200 mg to compensate for the normal daily iron losses by the mother.[86] Thus,
the normal expectant woman needs to absorb an average of 3.5 mg/day of iron. In actuality,
the iron requirements are not constant but increase remarkably during the third trimester to 6
to 7 mg/day. The fetus receives its iron through active transport, primarily during the last
trimester. Adequate iron transport to the fetus is maintained despite severe maternal iron
deficiency. Thus, there is no correlation between maternal and fetal hemoglobin
concentrations.

Currently, whether the nonanemic gravida should receive routine iron supplementation is
controversial. Most American obstetricians favor the practice, whereas those in Europe
generally consider it unnecessary. A recent Cochrane review concluded the evidence for
either a beneficial or harmful effect on pregnancy outcome is inconclusive.[87] With the
availability of serum ferritin levels that closely mirror body iron stores, it has become
apparent that the unsupplemented patient, although not always anemic, is frequently
significantly iron deficient at term. Romslo et al. demonstrated that unsupplemented women
who are not anemic at the beginning of gestation have a significant drop in hemoglobin
concentration, serum iron, serum ferritin, and transferrin saturation by term.[88] This suggests
that the majority of women have insufficient iron stores to meet the demands of pregnancy.
The recommended dose for iron supplementation is 30 mg elemental iron daily. More
recently Makrides et al.[89] used a lower dose of iron supplementation (20 mg of elemental
iron) starting at 20 weeks' gestation and showed similar improvements. Supplemented
women were less likely to demonstrate anemia and iron deficiency at delivery and iron
deficiency at 6 months postpartum as compared with women not given routine additional
iron, unless they were diagnosed with anemia at 28 weeks' gestation ( Table 3-6 ). In
addition, the incidence of side effects was not different in this placebo-controlled trial with
greater than 80-percent compliance. Still, no differences in pregnancy or neonatal outcomes
were found.[89]

Table 3-6 -- Effect of Iron Supplementation During Pregnancy

IRON-SUPPLEMENTED GROUP PLACEBO GROUP
Hemoglobin (g/dl) <20weeks 13.1 13.0
 IRON-SUPPLEMENTED GROUP PLACEBO GROUP
Maternal status @ delivery
Hemoglobin (g/dl) 12.7 12.0[*]
Serum ferritin (μg/L) 21 14[*]
Iron deficiency 35% 58%[*]
Iron deficiency 3% 11%[*]
anemia
Maternal status @ 6 months
Hemoglobin (g/dl) 13.5 13.4
Serum ferritin (μg/L) 34 26[*]
Iron deficiency 16% 29%[*]
Iron deficiency anemia 2.6% 1.7%
Adapted from Makrides M, Crowther C, Gibson R, et al: Efficacy and tolerability of low-dose
iron supplements during pregnancy: a randomized controlled trial. Am J Clin Nutr 78:145,
2003.
* Significant change between two groups.

It is important to remember that the purpose of iron supplementation during pregnancy is not
only to raise or even maintain the maternal hemoglobin level, but the goal is also to maintain
or restore normal maternal iron levels. Therefore, supplementation is often needed, but rarely
needs to be started before 20 to 28 weeks. Taking iron before 20 weeks can worsen the
nausea and vomiting of pregnancy. If a woman enters pregnancy with iron deficiency anemia
or if diagnosed with anemia, she will need to take additional iron. Available iron supplements
include ferrous sulfate 325 mg (65 mg elemental iron), ferrous gluconate 325 mg (35 mg
elemental iron), and ferrous fumarate 325 mg (107 mg elemental iron). The usual dose to
treat iron deficiency anemia is ferrous sulfate 325 mg bid (130 mg of elemental iron daily),
along with a stool softener such as docusate 100 mg bid. Previously, intravenous iron therapy
was rarely given due to potential serious side effects associated with intravenous iron
dextrans. However, recent studies have shown that intravenous iron sucrose can be given
without serious sequalae; but it had limited benefit versus oral administration in reliable
patients without abnormalities in iron absorption.[89a]

IRON DEFICIENCY ANEMIA

During a singleton pregnancy, maternal plasma volume gradually expands by approximately

50 percent (1,000 ml) (see Chapter 3 ). The total red blood cell (RBC) mass also increases,
but only by approximately 300 mg (25 percent), and this starts later in pregnancy.[61] It is not
surprising, therefore, that hemoglobin and hematocrit levels usually fall during gestation.
These changes are not necessarily pathologic but usually represent a physiologic alteration of
pregnancy. By 6 weeks postpartum, in the absence of excessive blood loss during the
puerperium, hemoglobin and hematocrit levels have returned to normal, if the mother has
adequate iron stores.
Most researchers and clinicians diagnose anemia when the hemoglobin concentration is less
than 11 g/dl or the hematocrit is less than 32 percent. Using these criteria, 50 percent of
pregnant women are anemic. The incidence of anemia changes depending on the population
studied. It is unfortunate that this problem is often ignored. In the developing nations, iron
deficiency is an overwhelming problem. Worldwide there are many maternal deaths because
of excessive blood loss in women who were already anemic. The previously cited arbitrary
cutoff for hemoglobin/hematocrit may need to be adjusted. Beaton[62] suggests that these
numbers should be adjusted downward and different targets should be established for
different times in pregnancy. As pregnancy progresses, hemoglobin levels are often in the
range of 10 to 10.5 g/dl in the late second and early third trimesters. These patients, if iron
stores are present, do regain their normal hemoglobin/hematocrit postpartum. Causes of
anemia in pregnancy are shown in the box “Causes of Anemia During Pregnancy.”

Causes of Anemia During Pregnancy

Common causes—85% of anemia
Physiologic anemia
Iron deficiency

Uncommon causes
Folic acid deficiency
Hemoglobinopathies
Sickle cell disease
Hemoglonin SC
β-Thalassemia minor

Bariatric surgery
Gastrointestinal bleeding

Rare causes
Hemoglobinpathies
β-Thalassemia major
α-Thalassemia
Vitamin B-12 deficiency
Syndromes of chronic hemolysis
Hereditary spherocytosis
Paroxysmal nocturnal hemoglobinuria

Hematologic malignancy

Approximately 75 percent of anemias that occur during pregnancy are secondary to iron
deficiency.[63] Ho and co-investigators[64] performed elaborate hematologic evaluations of 221
gravidas at term in Taiwan. None of the studied patients received an added iron preparation
during gestation. Of the previously nonanemic patients, 10.4 percent developed clinical
anemia after a full-term delivery. Of these 23 patients, 11 (47.8 percent) developed florid iron
deficiency anemia, and another 11 demonstrated moderate iron depletion.[65] The other
anemic patient in the group had folate deficiency. Of the 198 non-anemic gravidas at term,
46.5 percent showed evidence of iron depletion even though they had a normal hematocrit.
[64]

To distinguish the normal physiologic changes of pregnancy from those of pathologic iron
deficiency, one must understand the normal iron requirements of pregnancy ( Table 40-2 )
and the proper use of hematologic laboratory parameters. In adult women, iron stores are
located in the bone marrow, liver and spleen in the form of ferritin. Ferritin constitutes
approximately 25 percent (500 mg) of the 2-g of iron stores found in the normal woman.
Approximately 65 percent of stored iron is located in the circulating RBCs. [63] [65] [66] [67] If the
dietary iron intake is poor, the interval between pregnancies is short, or the delivery is
complicated by hemorrhage, iron deficiency anemia readily and rapidly develops.

Table 40-2 -- Iron Requirements for Pregnancy and the Puerperium

FUNCTION REQUIREMENT
Increased red blood cell mass 450 mg
Fetus and placenta 360 mg
Vaginal delivery 190 mg
Lactation 1 mg/day

The first pathologic change to occur in iron deficiency anemia is the depletion of bone
marrow, liver, and spleen iron stores. The serum iron level falls, as does the percentage
saturation of transferrin. The total iron-binding capacity rises, because this is a reflection of
unbound transferrin. A falling hemoglobin and hematocrit follow. Microcytic hypochromic
RBCs are released into the circulation. If iron deficiency is combined with folate or vitamin
β12 deficiency, normocytic and normochromic RBCs are observed on the peripheral blood
smear.

Care must be taken when using laboratory parameters to establish the diagnosis of iron
deficiency anemia during gestation. A serum iron concentration less than 60 mg/dl with less
than 16 percent saturation of transferrin is suggestive of iron deficiency. Conversely, a single
normal serum iron concentration does not rule out iron deficiency. For example, a patient
may take iron for several days, and this may result in a transiently normal serum iron
concentration while iron stores are still negligible. An increase in iron-binding capacity is not
reliable, because 15 percent of pregnant women without iron deficiency show an increase in
this parameter.[68] If a patient has been iron deficient for an extended period of time, her
serum iron level can rise before she has depleted her iron stores. The ferritin level indicates
the total status of her iron stores. Serum ferritin levels normally decrease minimally during
pregnancy. However, a significantly reduced ferritin concentration is indicative of iron
deficiency anemia and is the best parameter to judge the degree of iron deficiency. Ferritin
levels are variable and can change 25 percent from one day to the next.[69] Harthoorn-
Lasthuizen et al.[70] examined erythrocyte zinc protoporphyrin testing in pregnancy. They
found that serum ferritin levels did not predict the development of iron-deficient
erythropoiesis. However, erythrocyte zinc protoporphyrin measurements did help determine
which patients were developing iron deficiency before they developed frank anemia, and
these patients benefited from iron therapy.[70] Van de Broek et al.[71] believed that the
erythrocyte zinc protoporphyrin level was not particularly helpful and that a serum ferritin of
less than 30 mg/L was more than adequate to determine iron deficiency.

Ahluwalia[72] believes that measuring serum transferrin receptors can give a better index of
true iron status. Ferritin can be elevated in acute and chronic infections, whereas transferrin
receptors do not change in response to an infection. This is important in countries where
chronic infection is common in pregnant women. Also receptor concentrations are not
confounded by the hemodynamic changes of pregnancy. This test is not yet readily available
but may help us in the future to detect iron-deficient patients.[72]

Finally, when hematologic parameters remain confusing, bone marrow aspiration usually
provides the definitive diagnosis. The procedure, however, is rarely necessary.

Whether all women should receive prophylactic iron in addition to that contained in prenatal
vitamins during pregnancy remains controversial. Long[73] believes that the physiologic
changes of pregnancy are responsible for much of the decrease in hematocrit and, unless the
patient is symptomatic or the hematocrit is very low, iron supplementation is unnecessary. In
reviewing the Cochrane database, Millman et al.[74] found that 20 percent of fertile women
have iron stores greater than 500 mg, which is the required minimum for pregnancy. They
also noted that 40 percent of women have iron stores between 100 and 500 mg, and 40
percent have virtually no iron stores. Based on this data, most women do need some iron
supplementation.[74] There is no consensus, however, on how much iron supplementation may
be needed in patients with iron deficiency.

In pregnancy, iron absorption from the duodenum increases, providing 1.3 to 2.6 mg of
elemental iron daily. [75] [76] An acid environment in the duodenum helps this absorption.
Therefore, the frequent ingestion of antacid medications, commonly used by many patients,
decreases the absorption of iron. Chronic use of H2 blockers and proton pump inhibitors also
diminishes iron absorption. Vitamin C, in addition to the iron, may increase the acid
environment of the stomach and increase absorption. In patients who do not show clear signs
of iron deficiency, it is uncertain whether prophylactic iron, in addition to what is in prenatal
vitamins, leads to an increased hemoglobin concentration at term. Iron prophylaxis, however,
is safe as only amounts that can be used are absorbed. With the exception of dyspepsia and
constipation, side effects are few. One 325-mg tablet of ferrous sulfate daily provides
adequate prophylaxis. It contains 60 mg of elemental iron, 10 percent of which is absorbed. If
the iron is not needed, it will not be absorbed and will be excreted in the feces. The standard
generic iron tablets and the amount of elemental iron they provide are listed in Table 40-3 .

Table 40-3 -- Elemental Iron Available from Common Generic Iron Preparations
PREPARATION ELEMENTAL IRON (MG)
Ferrous gluconate 325 mg 37–39
Ferrous sulfate 325 mg 60–65
Ferrous fumarate 325 mg 107
In iron-deficient patients, one iron tablet three times daily has been recommended, although
the evidence-based source of this recommendation is difficult to ascertain. Most individuals
can absorb as much iron as they need taking iron twice daily. Iron should be taken 30 minutes
before meals to allow maximum absorption. However, when taken in this manner, dyspepsia
and nausea are more common. Therapy, therefore, must be individualized to maximize
patient compliance.

Zavaleta et al.[77] examined the use of zinc in addition to iron, because it is thought that zinc
may enhance hematopoiesis. However, they found that zinc, in addition to iron, did not
increase the hemoglobin concentration in patients. Young et al.[78] studied the effectiveness of
weekly iron supplementation. They found that weekly iron supplementation was almost as
effective as daily supplementation in raising the hemoglobin concentration in iron deficient
patients. This approach can be used in patients with less than optimal compliance.

For those patients who are noncompliant or are unable to take oral iron and are severely
anemic, intravenous iron can be given. Singh et al.[79] found that parenteral iron can be safely
given and significantly raises the hematocrit in patients. It also raises the serum ferritin. There
were no adverse effects in their study of patients.[79] Hallak et al.[80] examined the safety and
efficacy of parenteral iron administration. Of 26 patients receiving parenteral iron, only one
developed signs of mild allergy during the test dose and was excluded from the study. The
remaining 21 pregnant patients completed the course of therapy and received a mean of 1,000
mg of elemental iron. Their hemoglobin increased an average of 1.6 g/dl from the beginning
to the end of therapy and rose another 0.8 g/dl during the following 2 weeks. Ferritin levels
increased from 2.9 ng/ml at the beginning of therapy to 122.8 ng/dl by the end of
treatment.[80] Ferritin levels decreased to a mean of 109.4 ng/ml 2 weeks later. Only mild
transient side effects were noted. The authors concluded that parenteral iron therapy can be
used safely during pregnancy.[80]

Parenteral iron is indicated in those who cannot or will not take oral iron therapy and are not
anemic enough to require transfusion. In fact, by building iron stores in the patients before
delivery, we may be able to prevent a need for transfusion postpartum in the severely anemic
patient. Iron dextran comes in a concentration of 50 mg/ml. It can be given intramuscularly or
intravenously, although intramuscular injection is very painful. Iron dextran can result in
anaphylaxis, which is caused by dissociation of the iron component and carbohydrate
component. The reaction may be immediate or delayed. Therefore, a 0.5-ml test dose should
be given, and epinephrine should be readily available. Anaphylaxis usually occurs within
several minutes but may take 2 days to develop. In the past 3 years, our group has given iron
dextran to 14 patients. Two developed a severe reaction within minutes of the test dose.
Although neither patient developed shortness of breath, both exhibited severe bone pain and
myalgias. The dosage for iron dextran therapy is shown in Table 40-4 .

Table 40-4 -- Parenteral Iron Administration

MEDICATION DOSE PREPARATION
Iron dextran Total dose (ml) = 0.0442 (Desired hgb - 50 mg elemental
Observed hgb) × LBW + (0.26 × LBW). 100 iron/ml
mg/dose maximun
Iron sucrose 100 mg/dose, usually 1 dose/day, usually 10 20 mg elemental
doses needed iron/ml
MEDICATION DOSE PREPARATION
Sodium ferric 125 mg/dose, usually 1 dose/day, usually 8 12.5 mg of elemental
gluconate complex doses needed iron/ml
hgb, hemoglobin; LBW, lean body weight.

In addition to iron dextran, there are two newer parenteral iron preparations. Both of these
compounds have the disadvantage of requiring multiple doses to accomplish what can be
done with one dose of iron dextran. However, they have the advantage of less likelihood of a
severe adverse reaction. Iron sucrose complex is given intravenously with a maximum dose
of 100 g. It is usually given daily. Patients generally require 10 doses (1 g) to obtain the rise
in ferritin and subsequent rise in hemoglobin concentration that are desired. Sodium ferric
gluconate complex can be used similarly. The maximum dose is 125 mg. It is usually given
daily, and eight doses (1 g) are most often required to obtain the desired results. Sodium
ferric gluconate appears to have the least risk of adverse side effects. If the patient has
concomitant renal insufficiency, subcutaneous erythropoietin can be given to help raise the
hemoglobin concentration if iron stores have already been raised. These agents should be
used only in patients with severe iron deficiency who cannot absorb iron or who will not or
cannot take oral iron. A parenteral iron overdose can lead to hemosiderosis.

It is still not certain whether anemia results in an increased risk for poor pregnancy outcome.
In their literature review, Scholl and Hediger[81] concluded that anemia diagnosed in early
pregnancy is associated with preterm delivery and low birth weight. In this study, women
with iron deficiency anemia had twice the risk of preterm delivery and three times the risk of
delivering a low-birth-weight infant.[81] Preterm labor, however, is a multifactorial problem,
and there were many confounders in this study. Yip[82] reviewed the literature concerning
pregnancy outcome with anemia. He found through epidemiologic studies that there is an
association between moderate anemia and poor perinatal outcome, yet he was unable to
determine whether this relationship was causal.[82] Sifakis and Pharmakides[83] observed that
hemoglobin concentrations less than 6 g/dl are associated with preterm birth, spontaneous
abortion, low birth weight, and fetal deaths. Nevertheless, a mild to moderate anemia did not
appear to have any significant effect on fetal outcomes.[83] Hemminki and Starfield[84]
reviewed controlled trials, concluding that routine iron administration did not decrease
preterm labor or raise birth weight. Conversely, Stephansson et al.[85] found an increased risk
of stillbirth and growth-restricted infants in women with hemoglobin concentrations greater
than 14.6 g/dl at their prenatal visit.

In summary, iron deficiency is very prevalent in the general pregnant population. In

developing nations, severe anemia is alarmingly common and is a major cause of maternal
morbidity and mortality. Routine iron administration like that found in prenatal vitamins
should be used unless it is certain that the patient is iron replete. Iron prophylaxis can be
taken as one iron tablet daily, or as one study showed, can be given on a weekly basis. There
appears to be an association between poor pregnancy outcome and maternal anemia,
especially severe anemia. It is uncertain, however, if this is a causal relationship.

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